Cellular and Molecular Life Sciences

, Volume 76, Issue 19, pp 3801–3826 | Cite as

The molecular clock in the skin, its functionality, and how it is disrupted in cutaneous melanoma: a new pharmacological target?

  • Leonardo Vinícius Monteiro de Assis
  • Maria Nathalia Moraes
  • Ana Maria de Lauro CastrucciEmail author


The skin is the interface between the organism and the external environment, acting as its first barrier. Thus, this organ is constantly challenged by physical stimuli such as UV and infrared radiation, visible light, and temperature as well as chemicals and pathogens. To counteract the deleterious effects of the above-mentioned stimuli, the skin has complex defense mechanisms such as: immune and neuroendocrine systems; shedding of epidermal squamous layers and apoptosis of damaged cells; DNA repair; and pigmentary system. Here we have reviewed the current knowledge regarding which stimuli affect the molecular clock of the skin, the consequences to skin-related biological processes and, based on such knowledge, we suggest some therapeutic targets. We also explored the recent advances regarding the molecular clock disruption in melanoma, its impact on the carcinogenic process, and its therapeutic value in melanoma treatment.


Skin biology Skin physiology Biological and molecular clock Skin cancer Carcinogenic process 


Author contributions

LVMA designed the manuscript’s outline and content, reviewed the current literature, and drafted the first version of the manuscript. MNM and AMLC critically revised the manuscript and provided substantial contribution and improvements to the manuscript. All authors have approved the definitive version of the manuscript and agreed to be accountable for all aspects of the study in ensuring that questions related to the accuracy or integrity of any part of the study are appropriately investigated and resolved. Each person designated as authors qualify for authorship, and all those who qualify for authorship are listed.


This work was partially supported by the Sao Paulo Research Foundation (FAPESP, Grants 2018/14728-0 and 2012/50214-4), by the National Council of Technological and Scientific Development (CNPq, Grants 301293/2011-2 (AMLC), 303070/2015-3 and 428754/2018-0 (MNM)) and by the Coordination for the Improvement of Higher Education Personnel (CAPES). LVMA is a fellow of FAPESP (2018/16511-8 and 2013/24337-4) and MNM was a fellow of FAPESP (2014/16412-9).

Compliance with ethical standards

Conflict of interest

All authors state no conflict of interest that could have impacted the development of this study.


  1. 1.
    McLafferty E, Hendry C, Alistair F (2012) The integumentary system: anatomy, physiology and function of skin. Nurs Stand 27(3):35–42Google Scholar
  2. 2.
    Eyerich S, Eyerich K, Traidl-Hoffmann C, Biedermann T (2018) Cutaneous barriers and skin immunity: differentiating a connected network. Trends Immunol 39(4):315–327. Google Scholar
  3. 3.
    van Spyk E, Greenberg M, Mourad F, Andersen B (2016) Regulation of cutaneous stress response pathways by the circadian clock: from molecular pathways to therapeutic opportunities. In: Wondrak GT (ed) Skin stress response pathways: environmental factors and molecular opportunities, Springer, Cham, pp 281–300.
  4. 4.
    Sklar LR, Almutawa F, Lim HW, Hamzavi I (2013) Effects of ultraviolet radiation, visible light, and infrared radiation on erythema and pigmentation: a review. Photochem Photobiol Sci 12(1):54–64. Google Scholar
  5. 5.
    Fajuyigbe D, Young AR (2016) The impact of skin colour on human photobiological responses. Pigment Cell Melanoma Res 29(6):607–618. Google Scholar
  6. 6.
    Festa E, Fretz J, Berry R, Schmidt B, Rodeheffer M, Horowitz M, Horsley V (2011) Adipocyte lineage cells contribute to the skin stem cell niche to drive hair cycling. Cell 146(5):761–771. Google Scholar
  7. 7.
    Alexaki VI, Simantiraki D, Panayiotopoulou M, Rasouli O, Venihaki M, Castana O, Alexakis D, Kampa M, Stathopoulos EN, Castanas E (2012) Adipose tissue-derived mesenchymal cells support skin reepithelialization through secretion of KGF-1 and PDGF-BB: comparison with dermal fibroblasts. Cell Transplant 21(11):2441–2454. Google Scholar
  8. 8.
    Luo Y, Toyoda M, Nakamura M, Morohashi M (2002) Morphological analysis of skin in senescence-accelerated mouse P10. Med Mol Morphol 35(1):31–45. Google Scholar
  9. 9.
    Sun LQ, Lee DW, Zhang Q, Xiao W, Raabe EH, Meeker A, Miao D, Huso DL, Arceci RJ (2004) Growth retardation and premature aging phenotypes in mice with disruption of the SNF2-like gene, PASG. Genes Dev 18(9):1035–1046. Google Scholar
  10. 10.
    Gregory EL (1989) Thermoregulatory aspects of adipose tissue. Clin Dermatol 7(4):78–92. Google Scholar
  11. 11.
    Tansey EA, Johnson CD (2015) Recent advances in thermoregulation. Adv Physiol Educ 39(3):139–148. Google Scholar
  12. 12.
    Rivera-Gonzalez G, Shook B, Horsley V (2014) Adipocytes in skin health and disease. Cold Spring Harb Perspect Med. Google Scholar
  13. 13.
    Kruglikov IL, Scherer PE (2016) Dermal adipocytes: from irrelevance to metabolic targets? Trends Endocrinol Metab 27(1):1–10. Google Scholar
  14. 14.
    Zhang LJ, Chen SX, Guerrero-Juarez CF, Li F, Tong Y, Liang Y, Liggins M, Chen X, Chen H, Li M, Hata T, Zheng Y, Plikus MV, Gallo RL (2019) Age-related loss of innate immune antimicrobial function of dermal fat is mediated by transforming growth factor beta. Immunity 50(1):121–136.e125. Google Scholar
  15. 15.
    Ondrusova K, Fatehi M, Barr A, Czarnecka Z, Long W, Suzuki K, Campbell S, Philippaert K, Hubert M, Tredget E, Kwan P, Touret N, Wabitsch M, Lee KY, Light PE (2017) Subcutaneous white adipocytes express a light sensitive signaling pathway mediated via a melanopsin/TRPC channel axis. Sci Rep 7(1):16332. Google Scholar
  16. 16.
    Elias PM (2008) Skin barrier function. Curr Allergy Asthma Rep 8(4):299–305Google Scholar
  17. 17.
    Elias PM (2007) The skin barrier as an innate immune element. Semin Immunopathol 29(1):3–14Google Scholar
  18. 18.
    Krutmann J, Bouloc A, Sore G, Bernard BA, Passeron T (2017) The skin aging exposome. J Dermatol Sci 85(3):152–161. Google Scholar
  19. 19.
    Slominski AT, Zmijewski MA, Plonka PM, Szaflarski JP, Paus R (2018) How UV light touches the brain and endocrine system through skin, and why. Endocrinology 159(5):1992–2007. Google Scholar
  20. 20.
    Bangert C, Brunner PM, Stingl G (2011) Immune functions of the skin. Clin Dermatol 29(4):360–376. Google Scholar
  21. 21.
    Slominski AT, Zmijewski MA, Skobowiat C, Zbytek B, Slominski RM, Steketee JD (2012) Sensing the environment: regulation of local and global homeostasis by the skin’s neuroendocrine system. Adv Anat Embryol Cell Biol 212:v, vii, 1–115Google Scholar
  22. 22.
    Slominski A, Wortsman J (2000) Neuroendocrinology of the skin. Endocr Rev 21(5):457–487. Google Scholar
  23. 23.
    Brenner M, Hearing VJ (2008) The protective role of melanin against UV damage in human skin. Photochem Photobiol 84(3):539–549. Google Scholar
  24. 24.
    Gaddameedhi S, Selby CP, Kaufmann WK, Smart RC, Sancar A (2011) Control of skin cancer by the circadian rhythm. Proc Natl Acad Sci USA 108(46):18790–18795. Google Scholar
  25. 25.
    Gaddameedhi S, Selby CP, Kemp MG, Ye R, Sancar A (2015) The circadian clock controls sunburn apoptosis and erythema in mouse skin. J Invest Dermatol 135(4):1119–1127. Google Scholar
  26. 26.
    Dakup P, Gaddameedhi S (2017) Impact of the circadian clock on UV-induced DNA damage response and photocarcinogenesis. Photochem Photobiol 93(1):296–303. Google Scholar
  27. 27.
    Lin JY, Fisher DE (2007) Melanocyte biology and skin pigmentation. Nature 445(7130):843–850. Google Scholar
  28. 28.
    Solano F (2014) Melanins: skin pigments and much more—types, structural models, biological functions, and formation routes. N J Sci 2014:28. Google Scholar
  29. 29.
    Nasti TH, Timares L (2015) MC1R, eumelanin and pheomelanin: their role in determining the susceptibility to skin cancer. Photochem Photobiol 91(1):188–200. Google Scholar
  30. 30.
    Kovac J, Husse J, Oster H (2009) A time to fast, a time to feast: the crosstalk between metabolism and the circadian clock. Mol Cells 28(2):75–80. Google Scholar
  31. 31.
    Gerstner JR, Yin JC (2010) Circadian rhythms and memory formation. Nat Rev Neurosci 11(8):577–588. Google Scholar
  32. 32.
    Kyriacou CP, Hastings MH (2010) Circadian clocks: genes, sleep, and cognition. Trends Cogn Sci 14(6):259–267. Google Scholar
  33. 33.
    Perelis M, Ramsey KM, Bass J (2015) The molecular clock as a metabolic rheostat. Diabetes Obes Metab 17(Suppl 1):99–105. Google Scholar
  34. 34.
    Gerhart-Hines Z, Lazar MA (2015) Circadian metabolism in the light of evolution. Endocr Rev 36(3):289–304. Google Scholar
  35. 35.
    Brown SA (2016) Circadian metabolism: from mechanisms to metabolomics and medicine. Trends Endocrinol Metab 27(6):415–426. Google Scholar
  36. 36.
    Hogenesch JB, Ueda HR (2011) Understanding systems-level properties: timely stories from the study of clocks. Nat Rev Genet 12(6):407–416. Google Scholar
  37. 37.
    West AC, Bechtold DA (2015) The cost of circadian desynchrony: evidence, insights and open questions. BioEssays 37(7):777–788. Google Scholar
  38. 38.
    Ralph MR, Foster RG, Davis FC, Menaker M (1990) Transplanted suprachiasmatic nucleus determines circadian period. Science 247(4945):975–978Google Scholar
  39. 39.
    van den Pol AN (1980) The hypothalamic suprachiasmatic nucleus of rat: intrinsic anatomy. J Comp Neurol 191(4):661–702. Google Scholar
  40. 40.
    Panda S, Provencio I, Tu DC, Pires SS, Rollag MD, Castrucci AM, Pletcher MT, Sato TK, Wiltshire T, Andahazy M, Kay SA, Van Gelder RN, Hogenesch JB (2003) Melanopsin is required for non-image-forming photic responses in blind mice. Science 301(5632):525–527. Google Scholar
  41. 41.
    Panda S, Sato TK, Castrucci AM, Rollag MD, DeGrip WJ, Hogenesch JB, Provencio I, Kay SA (2002) Melanopsin (Opn4) requirement for normal light-induced circadian phase shifting. Science 298(5601):2213–2216. Google Scholar
  42. 42.
    Graham DM, Wong KY (2008) Melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs). In: Kolb H, Fernandez E, Nelson R (eds) Webvision: the organization of the retina and visual system, Salt Lake City (UT)Google Scholar
  43. 43.
    Kume K, Zylka MJ, Sriram S, Shearman LP, Weaver DR, Jin X, Maywood ES, Hastings MH, Reppert SM (1999) mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell 98(2):193–205Google Scholar
  44. 44.
    Shearman LP, Sriram S, Weaver DR, Maywood ES, Chaves I, Zheng B, Kume K, Lee CC, van der Horst GT, Hastings MH, Reppert SM (2000) Interacting molecular loops in the mammalian circadian clock. Science 288(5468):1013–1019Google Scholar
  45. 45.
    Gekakis N, Staknis D, Nguyen HB, Davis FC, Wilsbacher LD, King DP, Takahashi JS, Weitz CJ (1998) Role of the CLOCK protein in the mammalian circadian mechanism. Science 280(5369):1564–1569Google Scholar
  46. 46.
    Gallego M, Virshup DM (2007) Post-translational modifications regulate the ticking of the circadian clock. Nat Rev Mol Cell Biol 8(2):139–148. Google Scholar
  47. 47.
    Lee C, Etchegaray JP, Cagampang FR, Loudon AS, Reppert SM (2001) Posttranslational mechanisms regulate the mammalian circadian clock. Cell 107(7):855–867Google Scholar
  48. 48.
    Lowrey PL, Takahashi JS (2011) Genetics of circadian rhythms in mammalian model organisms. Adv Genet 74:175–230. Google Scholar
  49. 49.
    Takahashi JS (2017) Transcriptional architecture of the mammalian circadian clock. Nat Rev Genet 18(3):164–179. Google Scholar
  50. 50.
    Preitner N, Damiola F, Lopez-Molina L, Zakany J, Duboule D, Albrecht U, Schibler U (2002) The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110(2):251–260Google Scholar
  51. 51.
    Sato TK, Panda S, Miraglia LJ, Reyes TM, Rudic RD, McNamara P, Naik KA, FitzGerald GA, Kay SA, Hogenesch JB (2004) A functional genomics strategy reveals Rora as a component of the mammalian circadian clock. Neuron 43(4):527–537. Google Scholar
  52. 52.
    Zhang Y, Fang B, Emmett MJ, Damle M, Sun Z, Feng D, Armour SM, Remsberg JR, Jager J, Soccio RE, Steger DJ, Lazar MA (2015) Gene regulation. Discrete functions of nuclear receptor Rev-erbalpha couple metabolism to the clock. Science 348(6242):1488–1492. Google Scholar
  53. 53.
    Brown SA, Azzi A (2013) Peripheral circadian oscillators in mammals. Handb Exp Pharmacol 217:45–66. Google Scholar
  54. 54.
    Buhr ED, Takahashi JS (2013) Molecular components of the mammalian circadian clock. Handb Exp Pharmacol 217:3–27. Google Scholar
  55. 55.
    Purschke M, Laubach HJ, Anderson RR, Manstein D (2010) Thermal injury causes DNA damage and lethality in unheated surrounding cells: active thermal bystander effect. J Invest Dermatol 130(1):86–92. Google Scholar
  56. 56.
    Partch CL, Green CB, Takahashi JS (2014) Molecular architecture of the mammalian circadian clock. Trends Cell Biol 24(2):90–99. Google Scholar
  57. 57.
    Buijs FN, Leon-Mercado L, Guzman-Ruiz M, Guerrero-Vargas NN, Romo-Nava F, Buijs RM (2016) The circadian system: a regulatory feedback network of periphery and brain. Physiology (Bethesda) 31(3):170–181. Google Scholar
  58. 58.
    Albrecht U, Sun ZS, Eichele G, Lee CC (1997) A differential response of two putative mammalian circadian regulators, mper1 and mper2, to light. Cell 91(7):1055–1064Google Scholar
  59. 59.
    Porterfield VM, Piontkivska H, Mintz EM (2007) Identification of novel light-induced genes in the suprachiasmatic nucleus. BMC Neurosci 8:98. Google Scholar
  60. 60.
    Zhang R, Lahens NF, Ballance HI, Hughes ME, Hogenesch JB (2014) A circadian gene expression atlas in mammals: implications for biology and medicine. Proc Natl Acad Sci USA 111(45):16219–16224. Google Scholar
  61. 61.
    Astiz M, Heyde I, Oster H (2019) Mechanisms of communication in the mammalian circadian timing system. Int J Mol Sci 20(2):343. Google Scholar
  62. 62.
    Husse J, Eichele G, Oster H (2015) Synchronization of the mammalian circadian timing system: light can control peripheral clocks independently of the SCN clock: alternate routes of entrainment optimize the alignment of the body’s circadian clock network with external time. BioEssays 37(10):1119–1128. Google Scholar
  63. 63.
    Baron KG, Reid KJ (2014) Circadian misalignment and health. Int Rev Psychiatry 26(2):139–154. Google Scholar
  64. 64.
    Boivin DB, Boudreau P (2014) Impacts of shift work on sleep and circadian rhythms. Pathol Biol (Paris) 62(5):292–301. Google Scholar
  65. 65.
    Savvidis C, Koutsilieris M (2012) Circadian rhythm disruption in cancer biology. Mol Med 18(1):1249–1260. Google Scholar
  66. 66.
    Kelleher FC, Rao A, Maguire A (2014) Circadian molecular clocks and cancer. Cancer Lett 342(1):9–18. Google Scholar
  67. 67.
    Videnovic A, Lazar AS, Barker RA, Overeem S (2014) ‘The clocks that time us’—circadian rhythms in neurodegenerative disorders. Nat Rev Neurol 10(12):683–693. Google Scholar
  68. 68.
    Roenneberg T, Merrow M (2016) The circadian clock and human health. Curr Biol 26(10):R432–R443. Google Scholar
  69. 69.
    Tanioka M, Yamada H, Doi M, Bando H, Yamaguchi Y, Nishigori C, Okamura H (2009) Molecular clocks in mouse skin. J Invest Dermatol 129(5):1225–1231. Google Scholar
  70. 70.
    Plikus MV, Van Spyk EN, Pham K, Geyfman M, Kumar V, Takahashi JS, Andersen B (2015) The circadian clock in skin: implications for adult stem cells, tissue regeneration, cancer, aging, and immunity. J Biol Rhythms 30(3):163–182. Google Scholar
  71. 71.
    Dibner C, Schibler U, Albrecht U (2010) The mammalian circadian timing system: organization and coordination of central and peripheral clocks. Annu Rev Physiol 72:517–549. Google Scholar
  72. 72.
    Richards J, Gumz ML (2012) Advances in understanding the peripheral circadian clocks. FASEB J 26(9):3602–3613. Google Scholar
  73. 73.
    Husse J, Leliavski A, Tsang AH, Oster H, Eichele G (2014) The light-dark cycle controls peripheral rhythmicity in mice with a genetically ablated suprachiasmatic nucleus clock. FASEB J 28(11):4950–4960. Google Scholar
  74. 74.
    Izumo M, Pejchal M, Schook AC, Lange RP, Walisser JA, Sato TR, Wang X, Bradfield CA, Takahashi JS (2014) Differential effects of light and feeding on circadian organization of peripheral clocks in a forebrain Bmal1 mutant. Elife. Google Scholar
  75. 75.
    Husse J, Zhou X, Shostak A, Oster H, Eichele G (2011) Synaptotagmin10-Cre, a driver to disrupt clock genes in the SCN. J Biol Rhythms 26(5):379–389. Google Scholar
  76. 76.
    Wang H, van Spyk E, Liu Q, Geyfman M, Salmans ML, Kumar V, Ihler A, Li N, Takahashi JS, Andersen B (2017) Time-restricted feeding shifts the skin circadian clock and alters UVB-induced DNA damage. Cell Rep 20(5):1061–1072. Google Scholar
  77. 77.
    Zanello SB, Jackson DM, Holick MF (2000) Expression of the circadian clock genes clock and period1 in human skin. J Invest Dermatol 115(4):757–760. Google Scholar
  78. 78.
    Bjarnason GA, Jordan RC, Wood PA, Li Q, Lincoln DW, Sothern RB, Hrushesky WJ, Ben-David Y (2001) Circadian expression of clock genes in human oral mucosa and skin: association with specific cell-cycle phases. Am J Pathol 158(5):1793–1801. Google Scholar
  79. 79.
    Kawara S, Mydlarski R, Mamelak AJ, Freed I, Wang B, Watanabe H, Shivji G, Tavadia SK, Suzuki H, Bjarnason GA, Jordan RC, Sauder DN (2002) Low-dose ultraviolet B rays alter the mRNA expression of the circadian clock genes in cultured human keratinocytes. J Invest Dermatol 119(6):1220–1223. Google Scholar
  80. 80.
    Sandu C, Dumas M, Malan A, Sambakhe D, Marteau C, Nizard C, Schnebert S, Perrier E, Challet E, Pevet P, Felder-Schmittbuhl MP (2012) Human skin keratinocytes, melanocytes, and fibroblasts contain distinct circadian clock machineries. Cell Mol Life Sci 69(19):3329–3339. Google Scholar
  81. 81.
    Sandu C, Liu T, Malan A, Challet E, Pevet P, Felder-Schmittbuhl MP (2015) Circadian clocks in rat skin and dermal fibroblasts: differential effects of aging, temperature and melatonin. Cell Mol Life Sci 72(11):2237–2248. Google Scholar
  82. 82.
    Wu G, Ruben MD, Schmidt RE, Francey LJ, Smith DF, Anafi RC, Hughey JJ, Tasseff R, Sherrill JD, Oblong JE, Mills KJ, Hogenesch JB (2018) Population-level rhythms in human skin with implications for circadian medicine. Proc Natl Acad Sci USA 115(48):12313–12318. Google Scholar
  83. 83.
    Luber AJ, Ensanyat SH, Zeichner JA (2014) Therapeutic implications of the circadian clock on skin function. J Drugs Dermatol 13(2):130–134Google Scholar
  84. 84.
    Cho K, Gajula RP, Porter KI, Gaddameedhi S (2016) The cutaneous circadian clock as a determinant of environmental vulnerability: molecular pathways and chrono-pharmacological opportunities. In: Wondrak GT (ed) Skin stress response pathways: environmental factors and molecular opportunities. Springer, Cham, pp 415–432.
  85. 85.
    Gutierrez D, Arbesman J (2016) Circadian dysrhythmias, physiological aberrations, and the link to skin cancer. Int J Mol Sci 17(5):621. Google Scholar
  86. 86.
    Matsui MS, Pelle E, Dong K, Pernodet N (2016) Biological rhythms in the skin. Int J Mol Sci 17(6):801. Google Scholar
  87. 87.
    Slominski AT, Hardeland R, Reiter RJ (2015) When the circadian clock meets the melanin pigmentary system. J Invest Dermatol 135(4):943–945. Google Scholar
  88. 88.
    Miyashita Y, Moriya T, Kubota T, Yamada K, Asami K (2001) Expression of opsin molecule in cultured murine melanocyte. J Investig Dermatol Symp Proc 6(1):54–57Google Scholar
  89. 89.
    Lopes GJ, Gois CC, Lima LH, Castrucci AM (2010) Modulation of rhodopsin gene expression and signaling mechanisms evoked by endothelins in goldfish and murine pigment cell lines. Br J Med Biol Res 43(9):828–836Google Scholar
  90. 90.
    Tsutsumi M, Ikeyama K, Denda S, Nakanishi J, Fuziwara S, Aoki H, Denda M (2009) Expressions of rod and cone photoreceptor-like proteins in human epidermis. Exp Dermatol 18(6):567–570. Google Scholar
  91. 91.
    Wicks NL, Chan JW, Najera JA, Ciriello JM, Oancea E (2011) UVA phototransduction drives early melanin synthesis in human melanocytes. Curr Biol 21(22):1906–1911. Google Scholar
  92. 92.
    Kim HJ, Son ED, Jung JY, Choi H, Lee TR, Shin DW (2013) Violet light down-regulates the expression of specific differentiation markers through Rhodopsin in normal human epidermal keratinocytes. PLoS One 8(9):e73678. Google Scholar
  93. 93.
    de Assis LV, Moraes MN, da Silveira Cruz-Machado S (1863) Castrucci AM (2016) The effect of white light on normal and malignant murine melanocytes: a link between opsins, clock genes, and melanogenesis. Biochim Biophys Acta 1863(6 Pt A):1119–1133. Google Scholar
  94. 94.
    de Assis LVM, Moraes MN, Magalhaes-Marques KK, Castrucci AML (2018) Melanopsin and rhodopsin mediate UVA-induced immediate pigment darkening: unravelling the photosensitive system of the skin. Eur J Cell Biol 97(3):150–162. Google Scholar
  95. 95.
    Buscone S, Mardaryev AN, Raafs B, Bikker JW, Sticht C, Gretz N, Farjo N, Uzunbajakava NE, Botchkareva NV (2017) A new path in defining light parameters for hair growth: discovery and modulation of photoreceptors in human hair follicle. Lasers Surg Med 49(7):705–718. Google Scholar
  96. 96.
    Regazzetti C, Sormani L, Debayle D, Bernerd F, Tulic MK, De Donatis GM, Chignon-Sicard B, Rocchi S, Passeron T (2018) Melanocytes sense blue light and regulate pigmentation through opsin-3. J Invest Dermatol 138(1):171–178. Google Scholar
  97. 97.
    Castellano-Pellicena I, Uzunbajakava NE, Mignon C, Raafs B, Botchkarev VA, Thornton MJ (2018) Does blue light restore human epidermal barrier function via activation of Opsin during cutaneous wound healing? Lasers Surg Med.
  98. 98.
    Garza ZCF, Born M, Hilbers PAJ, van Riel NAW, Liebmann J (2018) Visible blue light therapy: molecular mechanisms and therapeutic opportunities. Curr Med Chem 25(40):5564–5577. Google Scholar
  99. 99.
    Young AR (1997) Chromophores in human skin. Phys Med Biol 42(5):789–802Google Scholar
  100. 100.
    Park S, Kim K, Bae IH, Lee SH, Jung J, Lee TR, Cho EG (2018) TIMP3 is a CLOCK-dependent diurnal gene that inhibits the expression of UVB-induced inflammatory cytokines in human keratinocytes. FASEB J 32(3):1510–1523. Google Scholar
  101. 101.
    Nikkola V, Gronroos M, Huotari-Orava R, Kautiainen H, Ylianttila L, Karppinen T, Partonen T, Snellman E (2018) Circadian time effects on NB-UVB-induced erythema in human skin in vivo. J Invest Dermatol 138(2):464–467. Google Scholar
  102. 102.
    Park J, Halliday GM, Surjana D, Damian DL (2010) Nicotinamide prevents ultraviolet radiation-induced cellular energy loss. Photochem Photobiol 86(4):942–948. Google Scholar
  103. 103.
    Chen AC, Damian DL, Halliday GM (2014) Oral and systemic photoprotection. Photodermatol Photoimmunol Photomed 30(2–3):102–111. Google Scholar
  104. 104.
    Sun Y, Wang P, Li H, Dai J (2018) BMAL1 and CLOCK proteins in regulating UVB-induced apoptosis and DNA damage responses in human keratinocytes. J Cell Physiol 233(12):9563–9574. Google Scholar
  105. 105.
    Yeom M, Lee H, Shin S, Park D, Jung E (2018) PER, a circadian clock component, mediates the suppression of MMP-1 expression in HaCaT keratinocytes by cAMP. Molecules 23(4):745. Google Scholar
  106. 106.
    Nikkola V, Miettinen ME, Karisola P, Gronroos M, Ylianttila L, Alenius H, Snellman E, Partonen T (2018) Ultraviolet B radiation modifies circadian time in epidermal skin and in subcutaneous adipose tissue. Photodermatol Photoimmunol Photomed.
  107. 107.
    Kim W, Kim DY, Lee KH (2019) Ultraviolet-C (UVC) ray acts as a synchronizing cue for circadian rhythm control in murine fibroblast. Biochem Biophys Res Commun.
  108. 108.
    Kawamura G, Hattori M, Takamatsu K, Tsukada T, Ninomiya Y, Benjamin I, Sassone-Corsi P, Ozawa T, Tamaru T (2018) Cooperative interaction among BMAL1, HSF1, and p53 protects mammalian cells from UV stress. Commun Biol 1:204. Google Scholar
  109. 109.
    de Assis LVM, Moraes MN, Castrucci AML (2017) Heat shock antagonizes UVA-induced responses in murine melanocytes and melanoma cells: an unexpected interaction. Photochem Photobiol Sci 16(5):633–648. Google Scholar
  110. 110.
    Poletini MO, de Assis LV, Moraes MN, Castrucci AM (2016) Estradiol differently affects melanin synthesis of malignant and normal melanocytes: a relationship with clock and clock-controlled genes. Mol Cell Biochem 421(1–2):29–39. Google Scholar
  111. 111.
    Hardman JA, Tobin DJ, Haslam IS, Farjo N, Farjo B, Al-Nuaimi Y, Grimaldi B, Paus R (2015) The peripheral clock regulates human pigmentation. J Invest Dermatol 135(4):1053–1064. Google Scholar
  112. 112.
    Romanovsky AA (2014) Skin temperature: its role in thermoregulation. Acta Physiol (Oxf) 210(3):498–507Google Scholar
  113. 113.
    Poletini MO, Moraes MN, Ramos BC, Jeronimo R, Castrucci AM (2015) TRP channels: a missing bond in the entrainment mechanism of peripheral clocks throughout evolution. Temperature (Austin) 2(4):522–534. Google Scholar
  114. 114.
    Wang H, Siemens J (2015) TRP ion channels in thermosensation, thermoregulation and metabolism. Temperature (Austin) 2(2):178–187. Google Scholar
  115. 115.
    Xu H, Ramsey IS, Kotecha SA, Moran MM, Chong JA, Lawson D, Ge P, Lilly J, Silos-Santiago I, Xie Y, DiStefano PS, Curtis R, Clapham DE (2002) TRPV3 is a calcium-permeable temperature-sensitive cation channel. Nature 418(6894):181–186. Google Scholar
  116. 116.
    Moraes MN, de Assis LVM, Magalhaes-Marques KK, Poletini MO, de Lima L, Castrucci AML (2017) Melanopsin, a canonical light receptor, mediates thermal activation of clock genes. Sci Rep 7(1):13977. Google Scholar
  117. 117.
    Perez-Cerezales S, Boryshpolets S, Afanzar O, Brandis A, Nevo R, Kiss V, Eisenbach M (2015) Involvement of opsins in mammalian sperm thermotaxis. Sci Rep 5:16146. Google Scholar
  118. 118.
    Leung NY, Montell C (2017) Unconventional roles of opsins. Annu Rev Cell Dev Biol.
  119. 119.
    Shen WL, Kwon Y, Adegbola AA, Luo J, Chess A, Montell C (2011) Function of rhodopsin in temperature discrimination in Drosophila. Science 331(6022):1333–1336. Google Scholar
  120. 120.
    Sokabe T, Chen HC, Luo J, Montell C (2016) A switch in thermal preference in drosophila larvae depends on multiple rhodopsins. Cell Rep 17(2):336–344. Google Scholar
  121. 121.
    Lee Y, Montell C (2013) Drosophila TRPA1 functions in temperature control of circadian rhythm in pacemaker neurons. J Neurosci 33(16):6716–6725. Google Scholar
  122. 122.
    Yosipovitch G, Xiong GL, Haus E, Sackett-Lundeen L, Ashkenazi I, Maibach HI (1998) Time-dependent variations of the skin barrier function in humans: transepidermal water loss, stratum corneum hydration, skin surface pH, and skin temperature. J Invest Dermatol 110(1):20–23. Google Scholar
  123. 123.
    Le Fur I, Reinberg A, Lopez S, Morizot F, Mechkouri M, Tschachler E (2001) Analysis of circadian and ultradian rhythms of skin surface properties of face and forearm of healthy women. J Invest Dermatol 117(3):718–724. Google Scholar
  124. 124.
    Sporl F, Schellenberg K, Blatt T, Wenck H, Wittern KP, Schrader A, Kramer A (2011) A circadian clock in HaCaT keratinocytes. J Invest Dermatol 131(2):338–348. Google Scholar
  125. 125.
    Tsuchiya Y, Akashi M, Nishida E (2003) Temperature compensation and temperature resetting of circadian rhythms in mammalian cultured fibroblasts. Genes Cells 8(8):713–720Google Scholar
  126. 126.
    Tamaru T, Hattori M, Honda K, Benjamin I, Ozawa T, Takamatsu K (2011) Synchronization of circadian Per2 rhythms and HSF1-BMAL1:CLOCK interaction in mouse fibroblasts after short-term heat shock pulse. PLoS One 6(9):e24521. Google Scholar
  127. 127.
    Flo A, Diez-Noguera A, Calpena AC, Cambras T (2014) Circadian rhythms on skin function of hairless rats: light and thermic influences. Exp Dermatol 23(3):214–216. Google Scholar
  128. 128.
    Benedict FG, Miles WR, Johnson A (1919) The temperature of the human skin. Proc Natl Acad Sci USA 5(6):218–222Google Scholar
  129. 129.
    Xu X, Karis AJ, Buller MJ, Santee WR (2013) Relationship between core temperature, skin temperature, and heat flux during exercise in heat. Eur J Appl Physiol 113(9):2381–2389. Google Scholar
  130. 130.
    Pronina TS, Rybakov VP (2011) Features of the circadian rhythm of skin temperature in eight- to nine-year-old children and young adults. Hum Physiol 37(4):478. Google Scholar
  131. 131.
    Park S-J, Waterhouse J (2014) A comparison between rhythms in forehead skin and rectal (core) temperature in sedentary subjects living in a thermally neutral environment. Biol Rhythm Res 45(3):415–428. Google Scholar
  132. 132.
    Costa CMA, Moreira DG, Sillero-Quintana M, Brito CJ, de Azambuja PG, de Andrade FA, Cano SP, Bouzas Marins JC (2018) Daily rhythm of skin temperature of women evaluated by infrared thermal imaging. J Therm Biol 72:1–9. Google Scholar
  133. 133.
    Scully CG, Karaboué A, Liu W-M, Meyer J, Innominato PF, Chon KH, Gorbach AM, Lévi F (2011) Skin surface temperature rhythms as potential circadian biomarkers for personalized chronotherapeutics in cancer patients. Interface Focus 1(1):48–60. Google Scholar
  134. 134.
    Cuesta M, Boudreau P, Cermakian N, Boivin DB (2017) Skin temperature rhythms in humans respond to changes in the timing of sleep and light. J Biol Rhythms 32(3):257–273. Google Scholar
  135. 135.
    Bracci M, Ciarapica V, Copertaro A, Barbaresi M, Manzella N, Tomasetti M, Gaetani S, Monaco F, Amati M, Valentino M, Rapisarda V, Santarelli L (2016) Peripheral skin temperature and circadian biological clock in shift nurses after a day off. Int J Mol Sci 17(5):623. Google Scholar
  136. 136.
    Martinez-Nicolas A, Madrid JA, Rol MÁ, Guaita M, Santamaría J, Montserrat JM (2017) Circadian impairment of distal skin temperature rhythm in patients with sleep-disordered breathing: the effect of CPAP. Sleep 40(6):zsx067. Google Scholar
  137. 137.
    Miyakoshi N, Itoi E, Sato K, Suzuki K, Matsuura H (1998) Skin temperature of the shoulder: circadian rhythms in normal and pathologic shoulders. J Shoulder Elbow Surg 7(6):625–628Google Scholar
  138. 138.
    Ndiaye MA, Nihal M, Wood GS, Ahmad N (2014) Skin, reactive oxygen species, and circadian clocks. Antioxid Redox Signal 20(18):2982–2996. Google Scholar
  139. 139.
    Coto-Montes A, Tomas-Zapico C, Rodriguez-Colunga MJ, Tolivia-Cadrecha D, Martinez-Fraga J, Hardeland R, Tolivia D (2001) Effects of the circadian mutation ‘tau’ on the Harderian glands of Syrian hamsters. J Cell Biochem 83(3):426–434Google Scholar
  140. 140.
    Sani M, Sebai H, Gadacha W, Boughattas NA, Reinberg A, Mossadok BA (2006) Catalase activity and rhythmic patterns in mouse brain, kidney and liver. Comp Biochem Physiol B Biochem Mol Biol 145(3–4):331–337. Google Scholar
  141. 141.
    Baydas G, Gursu MF, Yilmaz S, Canpolat S, Yasar A, Cikim G, Canatan H (2002) Daily rhythm of glutathione peroxidase activity, lipid peroxidation and glutathione levels in tissues of pinealectomized rats. Neurosci Lett 323(3):195–198Google Scholar
  142. 142.
    Davies MH, Bozigian HP, Merrick BA, Birt DF, Schnell RC (1983) Circadian variations in glutathione-S-transferase and glutathione peroxidase activities in the mouse. Toxicol Lett 19(1–2):23–27Google Scholar
  143. 143.
    Diaz-Munoz M, Hernandez-Munoz R, Suarez J, Chagoya de Sanchez V (1985) Day-night cycle of lipid peroxidation in rat cerebral cortex and their relationship to the glutathione cycle and superoxide dismutase activity. Neuroscience 16(4):859–863Google Scholar
  144. 144.
    Martin V, Sainz RM, Mayo JC, Antolin I, Herrera F, Rodriguez C (2003) Daily rhythm of gene expression in rat superoxide dismutases. Endocr Res 29(1):83–95Google Scholar
  145. 145.
    Hardeland R, Coto-Montes A, Poeggeler B (2003) Circadian rhythms, oxidative stress, and antioxidative defense mechanisms. Chronobiol Int 20(6):921–962Google Scholar
  146. 146.
    Wilking M, Ndiaye M, Mukhtar H, Ahmad N (2013) Circadian rhythm connections to oxidative stress: implications for human health. Antioxid Redox Signal 19(2):192–208. Google Scholar
  147. 147.
    Fanjul-Moles ML, López-Riquelme GO (2016) Relationship between oxidative stress, circadian rhythms, and AMD. Oxid Med Cell Longev 2016:7420637. Google Scholar
  148. 148.
    Shindo Y, Witt E, Han D, Epstein W, Packer L (1994) Enzymic and non-enzymic antioxidants in epidermis and dermis of human skin. J Invest Dermatol 102(1):122–124Google Scholar
  149. 149.
    Benedusi M, Frigato E, Beltramello M, Bertolucci C, Valacchi G (2018) Circadian clock as possible protective mechanism to pollution induced keratinocytes damage. Mech Ageing Dev 172:13–20. Google Scholar
  150. 150.
    Dong K, Pelle E, Yarosh DB, Pernodet N (2012) Sirtuin 4 identification in normal human epidermal keratinocytes and its relation to sirtuin 3 and energy metabolism under normal conditions and UVB-induced stress. Exp Dermatol 21(3):231–233. Google Scholar
  151. 151.
    Tamaru T, Hattori M, Ninomiya Y, Kawamura G, Vares G, Honda K, Mishra DP, Wang B, Benjamin I, Sassone-Corsi P, Ozawa T, Takamatsu K (2013) ROS stress resets circadian clocks to coordinate pro-survival signals. PLoS One 8(12):e82006. Google Scholar
  152. 152.
    Slominski A, Wortsman J, Luger T, Paus R, Solomon S (2000) Corticotropin releasing hormone and proopiomelanocortin involvement in the cutaneous response to stress. Physiol Rev 80(3):979–1020. Google Scholar
  153. 153.
    Slominski AT, Zmijewski MA, Zbytek B, Tobin DJ, Theoharides TC, Rivier J (2013) Key role of CRF in the skin stress response system. Endocr Rev 34(6):827–884. Google Scholar
  154. 154.
    Theoharides TC, Stewart JM, Taracanova A, Conti P, Zouboulis CC (2016) Neuroendocrinology of the skin. Rev Endocr Metab Disord 17(3):287–294. Google Scholar
  155. 155.
    Slominski A (2005) Neuroendocrine system of the skin. Dermatology (Basel, Switzerland) 211(3):199–208. Google Scholar
  156. 156.
    Slominski A, Wortsman J, Kohn L, Ain KB, Venkataraman GM, Pisarchik A, Chung JH, Giuliani C, Thornton M, Slugocki G, Tobin DJ (2002) Expression of hypothalamic–pituitary–thyroid axis related genes in the human skin. J Invest Dermatol 119(6):1449–1455. Google Scholar
  157. 157.
    Hazlerigg D (2012) The evolutionary physiology of photoperiodism in vertebrates. Prog Brain Res 199:413–422. Google Scholar
  158. 158.
    Acuna-Castroviejo D, Escames G, Venegas C, Diaz-Casado ME, Lima-Cabello E, Lopez LC, Rosales-Corral S, Tan DX, Reiter RJ (2014) Extrapineal melatonin: sources, regulation, and potential functions. Cell Mol Life Sci 71(16):2997–3025. Google Scholar
  159. 159.
    Slominski AT, Hardeland R, Zmijewski MA, Slominski RM, Reiter RJ, Paus R (2018) Melatonin: a cutaneous perspective on its production, metabolism, and functions. J Invest Dermatol 138(3):490–499. Google Scholar
  160. 160.
    Kim TK, Lin Z, Tidwell WJ, Li W, Slominski AT (2015) Melatonin and its metabolites accumulate in the human epidermis in vivo and inhibit proliferation and tyrosinase activity in epidermal melanocytes in vitro. Mol Cell Endocrinol 404:1–8. Google Scholar
  161. 161.
    Slominski A, Wortsman J, Tobin DJ (2005) The cutaneous serotoninergic/melatoninergic system: securing a place under the sun. FASEB J 19(2):176–194. Google Scholar
  162. 162.
    Slominski AT, Zmijewski MA, Semak I, Kim TK, Janjetovic Z, Slominski RM, Zmijewski JW (2017) Melatonin, mitochondria, and the skin. Cell Mol Life Sci 74(21):3913–3925. Google Scholar
  163. 163.
    Slominski A, Tobin DJ, Zmijewski MA, Wortsman J, Paus R (2008) Melatonin in the skin: synthesis, metabolism and functions. Trends Endocrinol Metab 19(1):17–24. Google Scholar
  164. 164.
    Slominski A, Baker J, Rosano TG, Guisti LW, Ermak G, Grande M, Gaudet SJ (1996) Metabolism of serotonin to N-acetylserotonin, melatonin, and 5-methoxytryptamine in hamster skin culture. J Biol Chem 271(21):12281–12286. Google Scholar
  165. 165.
    Slominski A, Pisarchik A, Semak I, Sweatman T, Wortsman J, Szczesniewski A, Slugocki G, McNulty J, Kauser S, Tobin DJ, Jing C, Johansson O (2002) Serotoninergic and melatoninergic systems are fully expressed in human skin. FASEB J 16(8):896–898. Google Scholar
  166. 166.
    Roseboom PH, Namboodiri MA, Zimonjic DB, Popescu NC, Rodriguez IR, Gastel JA, Klein DC (1998) Natural melatonin ‘knockdown’ in C57BL/6J mice: rare mechanism truncates serotonin N-acetyltransferase. Brain Res Mol Brain Res 63(1):189–197Google Scholar
  167. 167.
    Slominski A, Pisarchik A, Semak I, Sweatman T, Wortsman J (2003) Characterization of the serotoninergic system in the C57BL/6 mouse skin. Eur J Biochem 270(16):3335–3344Google Scholar
  168. 168.
    Slominski A, Pisarchik A, Zbytek B, Tobin DJ, Kauser S, Wortsman J (2003) Functional activity of serotoninergic and melatoninergic systems expressed in the skin. J Cell Physiol 196(1):144–153. Google Scholar
  169. 169.
    Slominski A, Fischer TW, Zmijewski MA, Wortsman J, Semak I, Zbytek B, Slominski RM, Tobin DJ (2005) On the role of melatonin in skin physiology and pathology. Endocrine 27(2):137–148. Google Scholar
  170. 170.
    Kobayashi H, Kromminga A, Dunlop TW, Tychsen B, Conrad F, Suzuki N, Memezawa A, Bettermann A, Aiba S, Carlberg C, Paus R (2005) A role of melatonin in neuroectodermal-mesodermal interactions: the hair follicle synthesizes melatonin and expresses functional melatonin receptors. FASEB J 19(12):1710–1712. Google Scholar
  171. 171.
    Slominski A, Pisarchik A, Wortsman J (2004) Expression of genes coding melatonin and serotonin receptors in rodent skin. Biochim Biophys Acta 1680(2):67–70. Google Scholar
  172. 172.
    Kim TK, Kleszczynski K, Janjetovic Z, Sweatman T, Lin Z, Li W, Reiter RJ, Fischer TW, Slominski AT (2013) Metabolism of melatonin and biological activity of intermediates of melatoninergic pathway in human skin cells. FASEB J 27(7):2742–2755. Google Scholar
  173. 173.
    Slominski AT, Semak I, Fischer TW, Kim TK, Kleszczynski K, Hardeland R, Reiter RJ (2017) Metabolism of melatonin in the skin: why is it important? Exp Dermatol 26(7):563–568. Google Scholar
  174. 174.
    Fischer TW, Sweatman TW, Semak I, Sayre RM, Wortsman J, Slominski A (2006) Constitutive and UV-induced metabolism of melatonin in keratinocytes and cell-free systems. FASEB J 20(9):1564–1566. Google Scholar
  175. 175.
    Skobowiat C, Brozyna AA, Janjetovic Z, Jeayeng S, Oak ASW, Kim TK, Panich U, Reiter RJ, Slominski AT (2018) Melatonin and its derivatives counteract the ultraviolet B radiation-induced damage in human and porcine skin ex vivo. J Pineal Res 65(2):e12501. Google Scholar
  176. 176.
    Slominski AT, Kleszczynski K, Semak I, Janjetovic Z, Zmijewski MA, Kim TK, Slominski RM, Reiter RJ, Fischer TW (2014) Local melatoninergic system as the protector of skin integrity. Int J Mol Sci 15(10):17705–17732. Google Scholar
  177. 177.
    Fischer TW, Kleszczynski K, Hardkop LH, Kruse N, Zillikens D (2013) Melatonin enhances antioxidative enzyme gene expression (CAT, GPx, SOD), prevents their UVR-induced depletion, and protects against the formation of DNA damage (8-hydroxy-2′-deoxyguanosine) in ex vivo human skin. J Pineal Res 54(3):303–312. Google Scholar
  178. 178.
    Janjetovic Z, Jarrett SG, Lee EF, Duprey C, Reiter RJ, Slominski AT (2017) Melatonin and its metabolites protect human melanocytes against UVB-induced damage: involvement of NRF2-mediated pathways. Sci Rep 7(1):1274. Google Scholar
  179. 179.
    Moraes MN, de Oliveira PM, Ribeiro Ramos BC, de Lima LH, de Lauro Castrucci AM (2014) Effect of light on expression of clock genes in Xenopus laevis melanophores. Photochem Photobiol 90(3):696–701. Google Scholar
  180. 180.
    Moraes MN, dos Santos LR, Mezzalira N, Poletini MO, Castrucci AM (2014) Regulation of melanopsins and Per1 by alpha -MSH and melatonin in photosensitive Xenopus laevis melanophores. Biomed Res Int 2014:654710. Google Scholar
  181. 181.
    Moraes MN, Ramos BC, Poletini MO, Castrucci AM (2015) Melanopsins: localization and phototransduction in Xenopus laevis melanophores. Photochem Photobiol 91(5):1133–1141. Google Scholar
  182. 182.
    Isoldi MC, Rollag MD, Castrucci AM, Provencio I (2005) Rhabdomeric phototransduction initiated by the vertebrate photopigment melanopsin. Proc Natl Acad Sci USA 102(4):1217–1221. Google Scholar
  183. 183.
    Hardman JA, Haslam IS, Farjo N, Farjo B, Paus R (2015) Thyroxine differentially modulates the peripheral clock: lessons from the human hair follicle. PLoS One 10(3):e0121878. Google Scholar
  184. 184.
    Balsalobre A, Brown SA, Marcacci L, Tronche F, Kellendonk C, Reichardt HM, Schutz G, Schibler U (2000) Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science 289(5488):2344–2347Google Scholar
  185. 185.
    Dickmeis T (2009) Glucocorticoids and the circadian clock. J Endocrinol 200(1):3–22. Google Scholar
  186. 186.
    Slominski A, Zbytek B, Szczesniewski A, Semak I, Kaminski J, Sweatman T, Wortsman J (2005) CRH stimulation of corticosteroids production in melanocytes is mediated by ACTH. Am J Physiol Endocrinol Metab 288(4):E701–E706. Google Scholar
  187. 187.
    Slominski A, Zbytek B, Semak I, Sweatman T, Wortsman J (2005) CRH stimulates POMC activity and corticosterone production in dermal fibroblasts. J Neuroimmunol 162(1–2):97–102. Google Scholar
  188. 188.
    Slominski A, Zbytek B, Nikolakis G, Manna PR, Skobowiat C, Zmijewski M, Li W, Janjetovic Z, Postlethwaite A, Zouboulis CC, Tuckey RC (2013) Steroidogenesis in the skin: implications for local immune functions. J Steroid Biochem Mol Biol 137:107–123. Google Scholar
  189. 189.
    Slominski AT, Manna PR, Tuckey RC (2015) On the role of skin in the regulation of local and systemic steroidogenic activities. Steroids 103:72–88. Google Scholar
  190. 190.
    Skobowiat C, Slominski AT (2015) UVB activates hypothalamic-pituitary-adrenal axis in C57BL/6 mice. J Invest Dermatol 135(6):1638–1648. Google Scholar
  191. 191.
    Skobowiat C, Postlethwaite AE, Slominski AT (2017) Skin exposure to ultraviolet B rapidly activates systemic neuroendocrine and immunosuppressive responses. Photochem Photobiol 93(4):1008–1015. Google Scholar
  192. 192.
    Han M, Ban JJ, Bae JS, Shin CY, Lee DH, Chung JH (2017) UV irradiation to mouse skin decreases hippocampal neurogenesis and synaptic protein expression via HPA axis activation. Sci Rep 7(1):15574. Google Scholar
  193. 193.
    Shaw CB, Milewich L, Sontheimer RD, Kaimal V (1986) Epidermal keratinocytes: a source of 5α- dihydrotestosterone production in human skin. J Clin Endocrinol Metab 62(4):739–746. Google Scholar
  194. 194.
    Milewich L, Shaw CB, Sontheimer RD (1988) Steroid metabolism by epidermal keratinocytes. Ann N Y Acad Sci 548:66–89Google Scholar
  195. 195.
    Holick MF (1994) McCollum Award Lecture, 1994: vitamin D–new horizons for the 21st century. Am J Clin Nutr 60(4):619–630. Google Scholar
  196. 196.
    Gutierrez-Monreal MA, Cuevas-Diaz Duran R, Moreno-Cuevas JE, Scott SP (2014) A role for 1alpha,25-dihydroxyvitamin d3 in the expression of circadian genes. J Biol Rhythms 29(5):384–388. Google Scholar
  197. 197.
    Slominski AT, Kim TK, Hobrath JV, Oak ASW, Tang EKY, Tieu EW, Li W, Tuckey RC, Jetten AM (2017) Endogenously produced nonclassical vitamin D hydroxy-metabolites act as “biased” agonists on VDR and inverse agonists on RORalpha and RORgamma. J Steroid Biochem Mol Biol 173:42–56. Google Scholar
  198. 198.
    Slominski AT, Kim TK, Takeda Y, Janjetovic Z, Brozyna AA, Skobowiat C, Wang J, Postlethwaite A, Li W, Tuckey RC, Jetten AM (2014) RORalpha and ROR gamma are expressed in human skin and serve as receptors for endogenously produced noncalcemic 20-hydroxy- and 20,23-dihydroxyvitamin D. FASEB J 28(7):2775–2789. Google Scholar
  199. 199.
    Chaiprasongsuk A, Janjetovic Z, Kim T-K, Holick MF, Tuckey RC, Panich U, Slominski AT (2018) 274 - Protective effects of novel derivatives of vitamin D3 and lumisterol against UVB-induced damage in human keratinocytes involve activation of Nrf2 and P53 defense mechanisms. Free Radic Biol Med 128:S116. Google Scholar
  200. 200.
    Asher G, Sassone-Corsi P (2015) Time for food: the intimate interplay between nutrition, metabolism, and the circadian clock. Cell 161(1):84–92. Google Scholar
  201. 201.
    Forni MF, Peloggia J, Braga TT, Chinchilla JEO, Shinohara J, Navas CA, Camara NOS, Kowaltowski AJ (2017) Caloric restriction promotes structural and metabolic changes in the skin. Cell Rep 20(11):2678–2692. Google Scholar
  202. 202.
    Bragazzi NL, Sellami M, Salem I, Conic R, Kimak M, Pigatto PDM, Damiani G (2019) Fasting and its impact on skin anatomy, physiology, and physiopathology: a comprehensive review of the literature. Nutrients 11(2):249. Google Scholar
  203. 203.
    Lee SK, Achieng E, Maddox C, Chen SC, Iuvone PM, Fukuhara C (2011) Extracellular low pH affects circadian rhythm expression in human primary fibroblasts. Biochem Biophys Res Commun 416(3–4):337–342. Google Scholar
  204. 204.
    Slominski A, Tobin DJ, Shibahara S, Wortsman J (2004) Melanin pigmentation in mammalian skin and its hormonal regulation. Physiol Rev 84(4):1155–1228. Google Scholar
  205. 205.
    Desotelle JA, Wilking MJ, Ahmad N (2012) The circadian control of skin and cutaneous photodamage. Photochem Photobiol 88(5):1037–1047. Google Scholar
  206. 206.
    Dupont E, Gomez J, Bilodeau D (2013) Beyond UV radiation: a skin under challenge. Int J Cosmet Sci 35(3):224–232. Google Scholar
  207. 207.
    Reinberg A, Sidi E, Ghata J (1965) Circadian reactivity rhythms of human skin to histamine or allergen and the adrenal cycle. J Allergy Clin Immunol 36(3):273–283. Google Scholar
  208. 208.
    Miller LS (2008) Toll-like receptors in skin. Adv Dermatol 24:71–87Google Scholar
  209. 209.
    Ando N, Nakamura Y, Aoki R, Ishimaru K, Ogawa H, Okumura K, Shibata S, Shimada S, Nakao A (2015) Circadian gene clock regulates psoriasis-like skin inflammation in mice. J Invest Dermatol 135(12):3001–3008. Google Scholar
  210. 210.
    Nakamura Y, Harama D, Shimokawa N, Hara M, Suzuki R, Tahara Y, Ishimaru K, Katoh R, Okumura K, Ogawa H, Shibata S, Nakao A (2011) Circadian clock gene Period2 regulates a time-of-day-dependent variation in cutaneous anaphylactic reaction. J Allergy Clin Immunol 127(4):1038–1045.e1031–1033. Google Scholar
  211. 211.
    Li WQ, Qureshi AA, Schernhammer ES, Han J (2013) Rotating night-shift work and risk of psoriasis in US women. J Invest Dermatol 133(2):565–567. Google Scholar
  212. 212.
    Malhotra N, Leyva-Castillo JM, Jadhav U, Barreiro O, Kam C, O’Neill NK, Meylan F, Chambon P, von Andrian UH, Siegel RM, Wang EC, Shivdasani R, Geha RS (2018) RORalpha-expressing T regulatory cells restrain allergic skin inflammation. Sci Immunol 3(21):eaao6923. Google Scholar
  213. 213.
    Vaughn AR, Clark AK, Sivamani RK, Shi VY (2018) Circadian rhythm in atopic dermatitis-pathophysiology and implications for chronotherapy. Pediatr Dermatol 35(1):152–157. Google Scholar
  214. 214.
    Patel T, Ishiuji Y, Yosipovitch G (2007) Nocturnal itch: why do we itch at night? Acta Derm Venereol 87(4):295–298. Google Scholar
  215. 215.
    Cho S, Shin MH, Kim YK, Seo JE, Lee YM, Park CH, Chung JH (2009) Effects of infrared radiation and heat on human skin aging in vivo. J Investig Dermatol Symp Proc 14(1):15–19. Google Scholar
  216. 216.
    Calapre L, Gray ES, Ziman M (2013) Heat stress: a risk factor for skin carcinogenesis. Cancer Lett 337(1):35–40. Google Scholar
  217. 217.
    Oklejewicz M, Destici E, Tamanini F, Hut RA, Janssens R, van der Horst GT (2008) Phase resetting of the mammalian circadian clock by DNA damage. Curr Biol 18(4):286–291. Google Scholar
  218. 218.
    Bee L, Marini S, Pontarin G, Ferraro P, Costa R, Albrecht U, Celotti L (2015) Nucleotide excision repair efficiency in quiescent human fibroblasts is modulated by circadian clock. Nucl Acids Res 43(4):2126–2137. Google Scholar
  219. 219.
    Manzella N, Bracci M, Strafella E, Staffolani S, Ciarapica V, Copertaro A, Rapisarda V, Ledda C, Amati M, Valentino M, Tomasetti M, Stevens RG, Santarelli L (2015) Circadian modulation of 8-oxoguanine DNA damage repair. Sci Rep 5:13752. Google Scholar
  220. 220.
    Geyfman M, Kumar V, Liu Q, Ruiz R, Gordon W, Espitia F, Cam E, Millar SE, Smyth P, Ihler A, Takahashi JS, Andersen B (2012) Brain and muscle Arnt-like protein-1 (BMAL1) controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis. Proc Natl Acad Sci USA 109(29):11758–11763. Google Scholar
  221. 221.
    Blanpain C, Fuchs E (2006) Epidermal stem cells of the skin. Annu Rev Cell Dev Biol 22:339–373. Google Scholar
  222. 222.
    Weger M, Diotel N, Dorsemans AC, Dickmeis T, Weger BD (2017) Stem cells and the circadian clock. Dev Biol 431(2):111–123. Google Scholar
  223. 223.
    Fuchs E (2008) Skin stem cells: rising to the surface. J Cell Biol 180(2):273–284. Google Scholar
  224. 224.
    Brown WR (1991) A review and mathematical analysis of circadian rhythms in cell proliferation in mouse, rat, and human epidermis. J Invest Dermatol 97(2):273–280Google Scholar
  225. 225.
    Stringari C, Wang H, Geyfman M, Crosignani V, Kumar V, Takahashi JS, Andersen B, Gratton E (2015) In vivo single-cell detection of metabolic oscillations in stem cells. Cell Rep 10(1):1–7. Google Scholar
  226. 226.
    Janich P, Toufighi K, Solanas G, Luis NM, Minkwitz S, Serrano L, Lehner B, Benitah SA (2013) Human epidermal stem cell function is regulated by circadian oscillations. Cell Stem Cell 13(6):745–753. Google Scholar
  227. 227.
    Lin KK, Kumar V, Geyfman M, Chudova D, Ihler AT, Smyth P, Paus R, Takahashi JS, Andersen B (2009) Circadian clock genes contribute to the regulation of hair follicle cycling. PLoS Genet 5(7):e1000573. Google Scholar
  228. 228.
    Geyfman M, Andersen B (2010) Clock genes, hair growth and aging. Aging (Albany NY) 2(3):122–128. Google Scholar
  229. 229.
    Slominski A, Paus R (1993) Melanogenesis is coupled to murine anagen: toward new concepts for the role of melanocytes and the regulation of melanogenesis in hair growth. J Invest Dermatol 101(1 Suppl):90s–97sGoogle Scholar
  230. 230.
    Slominski A, Wortsman J, Plonka PM, Schallreuter KU, Paus R, Tobin DJ (2005) Hair follicle pigmentation. J Invest Dermatol 124(1):13–21. Google Scholar
  231. 231.
    Al-Nuaimi Y, Hardman JA, Biro T, Haslam IS, Philpott MP, Toth BI, Farjo N, Farjo B, Baier G, Watson REB, Grimaldi B, Kloepper JE, Paus R (2014) A meeting of two chronobiological systems: circadian proteins Period1 and BMAL1 modulate the human hair cycle clock. J Invest Dermatol 134(3):610–619. Google Scholar
  232. 232.
    Plikus MV, Vollmers C, de la Cruz D, Chaix A, Ramos R, Panda S, Chuong CM (2013) Local circadian clock gates cell cycle progression of transient amplifying cells during regenerative hair cycling. Proc Natl Acad Sci USA 110(23):E2106–E2115. Google Scholar
  233. 233.
    Akashi M, Soma H, Yamamoto T, Tsugitomi A, Yamashita S, Yamamoto T, Nishida E, Yasuda A, Liao JK, Node K (2010) Noninvasive method for assessing the human circadian clock using hair follicle cells. Proc Natl Acad Sci USA 107(35):15643–15648. Google Scholar
  234. 234.
    Kervezee L, Cuesta M, Cermakian N, Boivin DB (2018) Simulated night shift work induces circadian misalignment of the human peripheral blood mononuclear cell transcriptome. Proc Natl Acad Sci USA 115(21):5540–5545. Google Scholar
  235. 235.
    Srour B, Plancoulaine S, Andreeva VA, Fassier P, Julia C, Galan P, Hercberg S, Deschasaux M, Latino-Martel P, Touvier M (2018) Circadian nutritional behaviours and cancer risk: new insights from the NutriNet-sante prospective cohort study: disclaimers. Int J Cancer 143(10):2369–2379. Google Scholar
  236. 236.
    Yamaguchi A, Matsumura R, Matsuzaki T, Nakamura W, Node K, Akashi M (2017) A simple method using ex vivo culture of hair follicle tissue to investigate intrinsic circadian characteristics in humans. Sci Rep 7(1):6824. Google Scholar
  237. 237.
    Hattammaru M, Tahara Y, Kikuchi T, Okajima K, Konishi K, Nakajima S, Sato K, Otsuka K, Sakura H, Shibata S, Nakaoka T (2019) The effect of night shift work on the expression of clock genes in beard hair follicle cells. Sleep Med.
  238. 238.
    Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153(6):1194–1217. Google Scholar
  239. 239.
    Kowalska E, Ripperger JA, Hoegger DC, Bruegger P, Buch T, Birchler T, Mueller A, Albrecht U, Contaldo C, Brown SA (2013) NONO couples the circadian clock to the cell cycle. Proc Natl Acad Sci USA 110(5):1592–1599. Google Scholar
  240. 240.
    Matsunaga N, Itcho K, Hamamura K, Ikeda E, Ikeyama H, Furuichi Y, Watanabe M, Koyanagi S, Ohdo S (2014) 24-hour rhythm of aquaporin-3 function in the epidermis is regulated by molecular clocks. J Invest Dermatol 134(6):1636–1644. Google Scholar
  241. 241.
    Sasaki H, Hokugo A, Wang L, Morinaga K, Ngo JT, Okawa H, Nishimura I (2019) Neuronal PAS domain 2 (Npas2)-deficient fibroblasts accelerate skin wound healing and dermal collagen reconstruction. Anat Rec.
  242. 242.
    Yosipovitch G, Sackett-Lundeen L, Goon A, Yiong Huak C, Leok Goh C, Haus E (2004) Circadian and ultradian (12 h) variations of skin blood flow and barrier function in non-irritated and irritated skin-effect of topical corticosteroids. J Invest Dermatol 122(3):824–829. Google Scholar
  243. 243.
    Stephenson LA, Wenger CB, O’Donovan BH, Nadel ER (1984) Circadian rhythm in sweating and cutaneous blood flow. Am J Physiol 246(3 Pt 2):R321–R324. Google Scholar
  244. 244.
    Denda M, Tsuchiya T (2000) Barrier recovery rate varies time-dependently in human skin. Br J Dermatol 142(5):881–884Google Scholar
  245. 245.
    Latreille J, Guinot C, Robert-Granie C, Le Fur I, Tenenhaus M, Foulley JL (2004) Daily variations in skin surface properties using mixed model methodology. Skin Pharmacol Physiol 17(3):133–140. Google Scholar
  246. 246.
    Verschoore M, Poncet M, Krebs B, Ortonne JP (1993) Circadian variations in the number of actively secreting sebaceous follicles and androgen circadian rhythms. Chronobiol Int 10(5):349–359Google Scholar
  247. 247.
    Jia Y, Zhou M, Huang H, Gan Y, Yang M, Ding R (2019) Characterization of circadian human facial surface lipid composition. Exp Dermatol.
  248. 248.
    Tsukahara K, Moriwaki S, Hotta M, Fujimura T, Kitahara T (2004) A study of diurnal variation in wrinkles on the human face. Arch Dermatol Res 296(4):169–174. Google Scholar
  249. 249.
    Gardner-Medwin JM, Macdonald IA, Taylor JY, Riley PH, Powell RJ (2001) Seasonal differences in finger skin temperature and microvascular blood flow in healthy men and women are exaggerated in women with primary Raynaud’s phenomenon. Br J Clin Pharmacol 52(1):17–23Google Scholar
  250. 250.
    Martinez-Nicolas A, Meyer M, Hunkler S, Madrid JA, Rol MA, Meyer AH, Schotzau A, Orgul S, Krauchi K (2015) Daytime variation in ambient temperature affects skin temperatures and blood pressure: ambulatory winter/summer comparison in healthy young women. Physiol Behav 149:203–211. Google Scholar
  251. 251.
    Black D, Del Pozo A, Lagarde JM, Gall Y (2000) Seasonal variability in the biophysical properties of stratum corneum from different anatomical sites. Skin Res Technol 6(2):70–76Google Scholar
  252. 252.
    Nam GW, Baek JH, Koh JS, Hwang JK (2015) The seasonal variation in skin hydration, sebum, scaliness, brightness and elasticity in Korean females. Skin Res Technol 21(1):1–8. Google Scholar
  253. 253.
    Qiu H, Long X, Ye JC, Hou J, Senee J, Laurent A, Bazin R, Flament F, Adam A, Coutet J, Piot B (2011) Influence of season on some skin properties: winter vs. summer, as experienced by 354 Shanghaiese women of various ages. Int J Cosmet Sci 33(4):377–383. Google Scholar
  254. 254.
    Hellemans L, Corstjens H, Neven A, Declercq L, Maes D (2003) Antioxidant enzyme activity in human stratum corneum shows seasonal variation with an age-dependent recovery. J Invest Dermatol 120(3):434–439. Google Scholar
  255. 255.
    Rogers J, Harding C, Mayo A, Banks J, Rawlings A (1996) Stratum corneum lipids: the effect of ageing and the seasons. Arch Dermatol Res 288(12):765–770. Google Scholar
  256. 256.
    Conti A, Rogers J, Verdejo P, Harding CR, Rawlings AV (1996) Seasonal influences on stratum corneum ceramide 1 fatty acids and the influence of topical essential fatty acids. Int J Cosmet Sci 18(1):1–12. Google Scholar
  257. 257.
    Ishikawa J, Shimotoyodome Y, Ito S, Miyauchi Y, Fujimura T, Kitahara T, Hase T (2013) Variations in the ceramide profile in different seasons and regions of the body contribute to stratum corneum functions. Arch Dermatol Res 305(2):151–162. Google Scholar
  258. 258.
    Nakagawa N, Sakai S, Matsumoto M, Yamada K, Nagano M, Yuki T, Sumida Y, Uchiwa H (2004) Relationship between NMF (lactate and potassium) content and the physical properties of the stratum corneum in healthy subjects. J Invest Dermatol 122(3):755–763. Google Scholar
  259. 259.
    Uter W, Gefeller O, Schwanitz HJ (1998) An epidemiological study of the influence of season (cold and dry air) on the occurrence of irritant skin changes of the hands. Br J Dermatol 138(2):266–272Google Scholar
  260. 260.
    Tupker RA, Coenraads PJ, Fidler V, De Jong MC, Van der Meer JB, De Monchy JG (1995) Irritant susceptibility and weal and flare reactions to bioactive agents in atopic dermatitis. II. Influence of season. Br J Dermatol 133(3):365–370Google Scholar
  261. 261.
    Kikuchi K, Kobayashi H, Le Fur I, Tschachler E, Tagami H (2002) The Winter season affects more severely the facial skin than the forearm skin: comparative biophysical studies conducted in the same Japanese females in later summer and winter. Exogenous Dermatol 1(1):32–38. Google Scholar
  262. 262.
    Andersen F, Andersen KH, Kligman AM (2003) Xerotic skin of the elderly: a summer versus winter comparison based on biophysical measurements. Exogenous Dermatol 2(4):190–194. Google Scholar
  263. 263.
    Engebretsen KA, Johansen JD, Kezic S, Linneberg A, Thyssen JP (2016) The effect of environmental humidity and temperature on skin barrier function and dermatitis. J Eur Acad Dermatol Venereol 30(2):223–249. Google Scholar
  264. 264.
    Mehling A, Fluhr JW (2006) Chronobiology: biological clocks and rhythms of the skin. Skin Pharmacol Physiol 19(4):182–189. Google Scholar
  265. 265.
    Hanahan D (2014) Rethinking the war on cancer. Lancet 383(9916):558–563. Google Scholar
  266. 266.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. Google Scholar
  267. 267.
    Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70Google Scholar
  268. 268.
    Mazzoccoli G, Colangelo T, Panza A, Rubino R, Tiberio C, Palumbo O, Carella M, Trombetta D, Gentile A, Tavano F, Valvano MR, Storlazzi CT, Macchia G, De Cata A, Bisceglia G, Capocefalo D, Colantuoni V, Sabatino L, Piepoli A, Mazza T (2016) Analysis of clock gene-miRNA correlation networks reveals candidate drivers in colorectal cancer. Oncotarget 7(29):45444–45461. Google Scholar
  269. 269.
    Filipski E, Subramanian P, Carriere J, Guettier C, Barbason H, Levi F (2009) Circadian disruption accelerates liver carcinogenesis in mice. Mutat Res 680(1–2):95–105. Google Scholar
  270. 270.
    Fu XJ, Li HX, Yang K, Chen D, Tang H (2016) The important tumor suppressor role of PER1 in regulating the cyclin-CDK-CKI network in SCC15 human oral squamous cell carcinoma cells. Onco Targets Ther 9:2237–2245. Google Scholar
  271. 271.
    Li HX, Fu XJ, Yang K, Chen D, Tang H, Zhao Q (2016) The clock gene PER1 suppresses expression of tumor-related genes in human oral squamous cell carcinoma. Oncotarget 7(15):20574–20583. Google Scholar
  272. 272.
    Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417(6892):949–954. Google Scholar
  273. 273.
    Winter SL, Bosnoyan-Collins L, Pinnaduwage D, Andrulis IL (2007) Expression of the circadian clock genes per1 and per2 in sporadic and familial breast tumors. Neoplasia (New York, NY) 9(10):797–800Google Scholar
  274. 274.
    Kuo SJ, Chen ST, Yeh KT, Hou MF, Chang YS, Hsu NC, Chang JG (2009) Disturbance of circadian gene expression in breast cancer. Virchows Arch 454(4):467–474. Google Scholar
  275. 275.
    Cao Q, Gery S, Dashti A, Yin D, Zhou Y, Gu J, Koeffler HP (2009) A role for the clock gene per1 in prostate cancer. Cancer Res 69(19):7619–7625. Google Scholar
  276. 276.
    Jung-Hynes B, Huang W, Reiter RJ, Ahmad N (2010) Melatonin resynchronizes dysregulated circadian rhythm circuitry in human prostate cancer cells. J Pineal Res 49(1):60–68. Google Scholar
  277. 277.
    Yang SL, Ren QG, Wen L, Hu JL, Wang HY (2017) Research progress on circadian clock genes in common abdominal malignant tumors. Oncol Lett 14(5):5091–5098. Google Scholar
  278. 278.
    Taniguchi H, Fernandez AF, Setien F, Ropero S, Ballestar E, Villanueva A, Yamamoto H, Imai K, Shinomura Y, Esteller M (2009) Epigenetic inactivation of the circadian clock gene BMAL1 in hematologic malignancies. Cancer Res 69(21):8447–8454. Google Scholar
  279. 279.
    Papagiannakopoulos T, Bauer MR, Davidson SM, Heimann M, Subbaraj L, Bhutkar A, Bartlebaugh J, Vander Heiden MG, Jacks T (2016) Circadian rhythm disruption promotes lung tumorigenesis. Cell Metab 24(2):324–331. Google Scholar
  280. 280.
    Shih MC, Yeh KT, Tang KP, Chen JC, Chang JG (2006) Promoter methylation in circadian genes of endometrial cancers detected by methylation-specific PCR. Mol Carcinog 45(10):732–740. Google Scholar
  281. 281.
    Lengyel Z, Lovig C, Kommedal S, Keszthelyi R, Szekeres G, Battyani Z, Csernus V, Nagy AD (2013) Altered expression patterns of clock gene mRNAs and clock proteins in human skin tumors. Tumour Biol 34(2):811–819. Google Scholar
  282. 282.
    de Assis LVM, Moraes MN, Magalhaes-Marques KK, Kinker GS, da Silveira Cruz-Machado S, Castrucci AML (2018) Non-metastatic cutaneous melanoma induces chronodisruption in central and peripheral circadian clocks. Int J Mol Sci 19(4):1065. Google Scholar
  283. 283.
    de Assis LVM, Kinker GS, Moraes MN, Markus RP, Fernandes PA, Castrucci AML (2018) Expression of the circadian clock gene bmal1 positively correlates with antitumor immunity and patient survival in metastatic melanoma. Front Oncol 8:185. Google Scholar
  284. 284.
    Kiessling S, Beaulieu-Laroche L, Blum ID, Landgraf D, Welsh DK, Storch KF, Labrecque N, Cermakian N (2017) Enhancing circadian clock function in cancer cells inhibits tumor growth. BMC Biol 15(1):13. Google Scholar
  285. 285.
    Masri S, Sassone-Corsi P (2018) The emerging link between cancer, metabolism, and circadian rhythms. Nat Med 24(12):1795–1803. Google Scholar
  286. 286.
    International Agency for Research on Cancer (IARC) (2010) Painting, firefighting, and shiftwork. IARC Monographs 98, p 812Google Scholar
  287. 287.
    Straif K, Baan R, Grosse Y, Secretan B, El Ghissassi F, Bouvard V, Altieri A, Benbrahim-Tallaa L, Cogliano V, Group WHO (2007) Carcinogenicity of shift-work, painting, and fire-fighting. Lancet Oncol 8(12):1065–1066Google Scholar
  288. 288.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ (2008) Cancer statistics, 2008. CA Cancer J Clin 58(2):71–96. Google Scholar
  289. 289.
    Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68(1):7–30. Google Scholar
  290. 290.
    Matthews NH, Li WQ, Qureshi AA, Cho E (2017) Etiology and Therapy, Chapter 1. Cutaneous Melanoma. Codon Publications, Brisbane. Google Scholar
  291. 291.
    Guy GP, Machlin SR, Ekwueme DU, Yabroff KR (2015) Prevalence and costs of skin cancer treatment in the U.S., 2002–2006 and 2007–2011. Am J Prev Med 48(2):183–187. Google Scholar
  292. 292.
    Markovic SN, Erickson LA, Rao RD, Weenig RH, Pockaj BA, Bardia A, Vachon CM, Schild SE, McWilliams RR, Hand JL, Laman SD, Kottschade LA, Maples WJ, Pittelkow MR, Pulido JS, Cameron JD, Creagan ET (2007) Malignant melanoma in the 21st century, part 1: epidemiology, risk factors, screening, prevention, and diagnosis. Mayo Clin Proc 82(3):364–380. Google Scholar
  293. 293.
    Vuong K, Armstrong BK, Weiderpass E, Lund E, Adami HO, Veierod MB, Barrett JH, Davies JR, Bishop DT, Whiteman DC, Olsen CM, Hopper JL, Mann GJ, Cust AE, McGeechan K, Investigators AMFS (2016) Development and external validation of a melanoma risk prediction model based on self-assessed risk factors. JAMA Dermatol 152(8):889–896. Google Scholar
  294. 294.
    Noone AM, Howlader N, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (2015) SEER cancer statistics review, 1975–2015, National Cancer Institute. Accessed Dec 2018
  295. 295.
    Stanton WR, Janda M, Baade PD, Anderson P (2004) Primary prevention of skin cancer: a review of sun protection in Australia and internationally. Health Promot Int 19(3):369–378. Google Scholar
  296. 296.
    Cancer Genome Atlas N (2015) Genomic classification of cutaneous melanoma. Cell 161(7):1681–1696. Google Scholar
  297. 297.
    Hayward NK, Wilmott JS, Waddell N, Johansson PA, Field MA, Nones K, Patch AM, Kakavand H, Alexandrov LB, Burke H, Jakrot V, Kazakoff S, Holmes O, Leonard C, Sabarinathan R, Mularoni L, Wood S, Xu Q, Waddell N, Tembe V, Pupo GM, De Paoli-Iseppi R, Vilain RE, Shang P, Lau LMS, Dagg RA, Schramm SJ, Pritchard A, Dutton-Regester K, Newell F, Fitzgerald A, Shang CA, Grimmond SM, Pickett HA, Yang JY, Stretch JR, Behren A, Kefford RF, Hersey P, Long GV, Cebon J, Shackleton M, Spillane AJ, Saw RPM, Lopez-Bigas N, Pearson JV, Thompson JF, Scolyer RA, Mann GJ (2017) Whole-genome landscapes of major melanoma subtypes. Nature 545(7653):175–180. Google Scholar
  298. 298.
    Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Borresen-Dale AL, Boyault S, Burkhardt B, Butler AP, Caldas C, Davies HR, Desmedt C, Eils R, Eyfjord JE, Foekens JA, Greaves M, Hosoda F, Hutter B, Ilicic T, Imbeaud S, Imielinski M, Jager N, Jones DT, Jones D, Knappskog S, Kool M, Lakhani SR, Lopez-Otin C, Martin S, Munshi NC, Nakamura H, Northcott PA, Pajic M, Papaemmanuil E, Paradiso A, Pearson JV, Puente XS, Raine K, Ramakrishna M, Richardson AL, Richter J, Rosenstiel P, Schlesner M, Schumacher TN, Span PN, Teague JW, Totoki Y, Tutt AN, Valdes-Mas R, van Buuren MM, van ‘t Veer L, Vincent-Salomon A, Waddell N, Yates LR, Australian Pancreatic Cancer Genome I, Consortium IBC, Consortium IM-S, PedBrain I, Zucman-Rossi J, Futreal PA, McDermott U, Lichter P, Meyerson M, Grimmond SM, Siebert R, Campo E, Shibata T, Pfister SM, Campbell PJ, Stratton MR (2013) Signatures of mutational processes in human cancer. Nature 500(7463):415–421.
  299. 299.
    Shain AH, Bastian BC (2016) From melanocytes to melanomas. Nat Rev Cancer 16(6):345–358. Google Scholar
  300. 300.
    Guterres AN, Herlyn M, Villanueva J (2019) Melanoma. In: eLS. Wiley, Chichester.
  301. 301.
    Schadendorf D, van Akkooi ACJ, Berking C, Griewank KG, Gutzmer R, Hauschild A, Stang A, Roesch A, Ugurel S (2018) Melanoma. Lancet 392(10151):971–984. Google Scholar
  302. 302.
    Song X, Zhao Z, Barber B, Farr AM, Ivanov B, Novich M (2015) Overall survival in patients with metastatic melanoma. Curr Med Res Opin 31(5):987–991. Google Scholar
  303. 303.
    Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O’Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA, Group B-S (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364(26):2507–2516. Google Scholar
  304. 304.
    Grimaldi AM, Simeone E, Ascierto PA (2014) The role of MEK inhibitors in the treatment of metastatic melanoma. Curr Opin Oncol 26(2):196–203. Google Scholar
  305. 305.
    Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion Sileni V, Lebbe C, Mandala M, Millward M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Casey M, Ouellet D, Martin AM, Le N, Patel K, Flaherty K (2014) Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 371(20):1877–1888. Google Scholar
  306. 306.
    Redman JM, Gibney GT, Atkins MB (2016) Advances in immunotherapy for melanoma. BMC Med 14:20. Google Scholar
  307. 307.
    Paluncic J, Kovacevic Z, Jansson PJ, Kalinowski D, Merlot AM, Huang ML, Lok HC, Sahni S, Lane DJ (1863) Richardson DR (2016) Roads to melanoma: key pathways and emerging players in melanoma progression and oncogenic signaling. Biochim Biophys Acta 4:770–784. Google Scholar
  308. 308.
    Brozyna AA, Jozwicki W, Skobowiat C, Jetten A, Slominski AT (2016) RORalpha and RORgamma expression inversely correlates with human melanoma progression. Oncotarget.
  309. 309.
    Kettner NM, Katchy CA, Fu L (2014) Circadian gene variants in cancer. Ann Med 46(4):208–220. Google Scholar
  310. 310.
    Shostak A (2017) Circadian clock, cell division, and cancer: from molecules to organism. Int J Mol Sci 18(4):873. Google Scholar
  311. 311.
    Kiessling S, Cermakian N (2017) The tumor circadian clock: a new target for cancer therapy? Fut Oncol 13(29):2607–2610. Google Scholar
  312. 312.
    Egeblad M, Nakasone ES, Werb Z (2010) Tumors as organs: complex tissues that interface with the entire organism. Dev Cell 18(6):884–901. Google Scholar
  313. 313.
    Al-Zoughbi W, Huang J, Paramasivan GS, Till H, Pichler M, Guertl-Lackner B, Hoefler G (2014) Tumor macroenvironment and metabolism. Semin Oncol 41(2):281–295. Google Scholar
  314. 314.
    Masri S, Papagiannakopoulos T, Kinouchi K, Liu Y, Cervantes M, Baldi P, Jacks T, Sassone-Corsi P (2016) Lung adenocarcinoma distally rewires hepatic circadian homeostasis. Cell 165(4):896–909. Google Scholar
  315. 315.
    Hojo H, Enya S, Arai M, Suzuki Y, Nojiri T, Kangawa K, Koyama S, Kawaoka S (2017) Remote reprogramming of hepatic circadian transcriptome by breast cancer. Oncotarget 8(21):34128–34140. Google Scholar
  316. 316.
    Aran D, Camarda R, Odegaard J, Paik H, Oskotsky B, Krings G, Goga A, Sirota M, Butte AJ (2017) Comprehensive analysis of normal adjacent to tumor transcriptomes. Nat Commun 8(1):1077. Google Scholar
  317. 317.
    Brozyna AA, Jozwicki W, Roszkowski K, Filipiak J, Slominski AT (2016) Melanin content in melanoma metastases affects the outcome of radiotherapy. Oncotarget 7(14):17844–17853. Google Scholar
  318. 318.
    Axelrod ML, Johnson DB, Balko JM (2018) Emerging biomarkers for cancer immunotherapy in melanoma. Semin Cancer Biol 52(Pt 2):207–215. Google Scholar
  319. 319.
    Hogan SA, Levesque MP, Cheng PF (2018) Melanoma immunotherapy: next-generation biomarkers. Front Oncol 8:178. Google Scholar
  320. 320.
    Sulli G, Rommel A, Wang X, Kolar MJ, Puca F, Saghatelian A, Plikus MV, Verma IM, Panda S (2018) Pharmacological activation of REV-ERBs is lethal in cancer and oncogene induced senescence. Nature 553(7688):351–355. Google Scholar
  321. 321.
    Gatti G, Lucini V, Dugnani S, Calastretti A, Spadoni G, Bedini A, Rivara S, Mor M, Canti G, Scaglione F, Bevilacqua A (2017) Antiproliferative and pro-apoptotic activity of melatonin analogues on melanoma and breast cancer cells. Oncotarget 8(40):68338–68353. Google Scholar
  322. 322.
    Slominski A, Pruski D (1993) Melatonin inhibits proliferation and melanogenesis in rodent melanoma cells. Exp Cell Res 206(2):189–194. Google Scholar
  323. 323.
    Fischer TW, Zmijewski MA, Zbytek B, Sweatman TW, Slominski RM, Wortsman J, Slominski A (2006) Oncostatic effects of the indole melatonin and expression of its cytosolic and nuclear receptors in cultured human melanoma cell lines. Int J Oncol 29(3):665–672Google Scholar
  324. 324.
    Kadekaro AL, Andrade LN, Floeter-Winter LM, Rollag MD, Virador V, Vieira W, Castrucci AM (2004) MT-1 melatonin receptor expression increases the antiproliferative effect of melatonin on S-91 murine melanoma cells. J Pineal Res 36(3):204–211Google Scholar
  325. 325.
    Kinker GS, Oba-Shinjo SM, Carvalho-Sousa CE, Muxel SM, Marie SKN, Markus RP, Fernandes PA (2016) Melatonergic system-based two-gene index is prognostic in human gliomas. J Pineal Res 60(1):84–94. Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Leonardo Vinícius Monteiro de Assis
    • 1
  • Maria Nathalia Moraes
    • 1
    • 2
  • Ana Maria de Lauro Castrucci
    • 1
    Email author
  1. 1.Laboratory of Comparative Physiology of Pigmentation, Department of Physiology, Institute of BiosciencesUniversity of São PauloSão PauloBrazil
  2. 2.School of Health ScienceUniversity Anhembi MorumbiSão PauloBrazil

Personalised recommendations