Sulforaphane and iberin are potent epigenetic modulators of histone acetylation and methylation in malignant melanoma



Growing evidence supports that isothiocyanates exert a wide range of bioactivities amongst of which is their capacity to interact with the epigenetic machinery in various cancers including melanoma. Our aim was to characterise the effect of sulforaphane and iberin on histone acetylation and methylation as a potential anti-melanoma strategy.


We have utilised an in vitro model of malignant melanoma [consisting of human (A375, Hs294T, VMM1) and murine (B16F-10) melanoma cell lines as well as a non-melanoma (A431) and a non-tumorigenic immortalised keratinocyte (HaCaT) cell line] exposed to sulforaphane or iberin. Cell viability was evaluated by the Alamar blue assay whilst total histone deacetylases and acetyltransferases activities were determined by the Epigenase HDAC Activity/Inhibition and EpiQuik HAT Activity/Inhibition assay kits, respectively. The expression levels of specific histone deacetylases and acetyltransferases together with those of lysine acetylation and methylation marks were obtained by western immunoblotting.


Overall, both sulforaphane and iberin were able to (1) reduce cell viability, (2) decrease total histone deacetylase activity and (3) modulate the expression levels of various histone deacetylases as well as acetyl and methyl transferases thus modulating the acetylation and methylation status of specific lysine residues on histones 3 and 4 in malignant melanoma cells.


Our findings highlight novel insights as to how sulforaphane and iberin differentially regulate the epigenetic response in ways compatible with their anticancer action in malignant melanoma.

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  1. 1.

    Sharma S, Kelly TK, Jones PA (2010) Epigenetics in cancer. Carcinogenesis 31:27–36

    CAS  Google Scholar 

  2. 2.

    Anestopoulos I, Voulgaridou GP, Georgakilas AG, Franco R, Pappa A, Panayiotidis MI (2015) Epigenetic therapy as a novel approach in hepatocellular carcinoma. Pharmacol Ther 145:103–119

    CAS  PubMed  Google Scholar 

  3. 3.

    Golbabapour S, Abdulla MA, Hajrezaei M (2011) A concise review on epigenetic regulation: insight into molecular mechanisms. Int J Mol Sci 12:8661–8694

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    West AC, Johnstone RW (2014) New and emerging HDAC inhibitors for cancer treatment. J Clin Invest 124:30–39

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Yan C, Boyd DD (2006) Histone H3 acetylation and H3 K4 methylation define distinct chromatin regions permissive for transgene expression. Mol Cell Biol 26:6357–6371

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Dawson MA, Kouzarides T (2012) Cancer epigenetics: from mechanism to therapy. Cell 150:12–27

    CAS  PubMed  Google Scholar 

  7. 7.

    Ziech D, Franco R, Pappa A, Malamou-Mitsi V, Georgakila S, Georgakilas AG et al (2010) The role of epigenetics in environmental and occupational carcinogenesis. Chem-Biol Interact 188:340–349

    CAS  PubMed  Google Scholar 

  8. 8.

    Ziech D, Franco R, Pappa A, Panayiotidis MI (2011) Reactive oxygen species (ROS)-induced genetic and epigenetic alterations in human carcinogenesis. Mutat Res 711:167–173

    CAS  PubMed  Google Scholar 

  9. 9.

    Franco R, Schoneveld O, Georgakilas AG, Panayiotidis MI (2008) Oxidative stress, DNA methylation and carcinogenesis. Cancer Lett 266:6–11

    CAS  PubMed  Google Scholar 

  10. 10.

    Lee JJ, Murphy GF, Lian CG (2014) Melanoma epigenetics: novel mechanisms, markers, and medicines. Lab Invest 94:822

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Shannan B, Perego M, Somasundaram R, Herlyn M (2016) Heterogeneity in melanoma. Cancer Treat Res 167:1–15

    PubMed  Google Scholar 

  12. 12.

    Zhang X-Y, Zhang P-Y (2016) Genetics and epigenetics of melanoma. Oncol Lett 12:3041–3044

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Pandey M, Kaur P, Shukla S, Abbas A, Fu P, Gupta S (2012) Plant flavone apigenin inhibits HDAC and remodels chromatin to induce growth arrest and apoptosis in human prostate cancer cells: in vitro and in vivo study. Mol Carcinog 51:952–962

    CAS  PubMed  Google Scholar 

  14. 14.

    Pandey M, Shukla S, Gupta S (2010) Promoter demethylation and chromatin remodeling by green tea polyphenols leads to re-expression of GSTP1 in human prostate cancer cells. Int J Cancer 126:2520–2533

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Majid S, Dar AA, Shahryari V, Hirata H, Ahmad A, Saini S et al (2010) Genistein reverses hypermethylation and induces active histone modifications in tumor suppressor gene B-Cell translocation gene 3 in prostate cancer. Cancer 116:66–76

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Fu L-J, Ding Y-B, Wu L-X, Wen C-J, Qu Q, Zhang X et al (2014) The effects of lycopene on the methylation of the GSTP1 promoter and global methylation in prostatic cancer cell lines PC3 and LNCaP. Int J Endocrinol 2014:620165

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Lee W-J, Chen Y-R, Tseng T-H (2011) Quercetin induces FasL-related apoptosis, in part, through promotion of histone H3 acetylation in human leukemia HL-60 cells. Oncol Rep 25:583–591

    CAS  PubMed  Google Scholar 

  18. 18.

    Azimi A, Hagh MF, Talebi M, Yousefi B, Baradaran B, Movassaghpour AA et al (2015) Time-and concentration-dependent effects of resveratrol on miR 15a and miR16-1 expression and apoptosis in the CCRF-CEM acute lymphoblastic leukemia cell line. Asian Pac J Cancer Prev 16:6463–6468

    PubMed  Google Scholar 

  19. 19.

    Mitsiogianni M, Amery T, Franco R, Zoumpourlis V, Pappa A, Panayiotidis MI (2018) From chemo-prevention to epigenetic regulation: the role of isothiocyanates in skin cancer prevention. Pharmacol Ther 190:187–201

    CAS  PubMed  Google Scholar 

  20. 20.

    Mitsiogianni M, Koutsidis G, Mavroudis N, Trafalis DT, Botaitis S, Franco R et al (2019) The role of isothiocyanates as cancer chemo-preventive. Chemo-Ther Anti-Melanoma Agents Antioxidants 8(4):106

    CAS  Google Scholar 

  21. 21.

    Cheng Y-M, Tsai C-C, Hsu Y-C (2016) Sulforaphane, a dietary isothiocyanate, induces G2/M arrest in Cervical cancer cells through CyclinB1 downregulation and GADD45β/CDC2 Association. Int J Mol Sci 17:1530

    PubMed Central  Google Scholar 

  22. 22.

    Mondal A, Biswas R, Rhee Y-H, Kim J, Ahn J-C (2016) Sulforaphene promotes Bax/Bcl2, MAPK-dependent human gastric cancer AGS cells apoptosis and inhibits migration via EGFR, p-ERK1/2 down-regulation. Gen Physiol Biophys 35:25–34

    CAS  PubMed  Google Scholar 

  23. 23.

    Cho S-D, Li G, Hu H, Jiang C, Kang K-S, Lee Y-S et al (2005) Involvement of c-Jun N-terminal kinase in G2/M arrest and caspase-mediated apoptosis induced by sulforaphane in DU145 prostate cancer cells. Nutr Cancer 52:213–224

    CAS  PubMed  Google Scholar 

  24. 24.

    Lee YJ, Lee SH (2017) Pro-oxidant activity of sulforaphane and cisplatin potentiates apoptosis and simultaneously promotes autophagy in malignant mesothelioma cells. Mol Med Rep 16:2133–2141

    CAS  PubMed  Google Scholar 

  25. 25.

    Yang F, Wang F, Liu Y, Wang S, Li X, Huang Y et al (2018) Sulforaphane induces autophagy by inhibition of HDAC6-mediated PTEN activation in triple negative breast cancer cells. Life Sci 213:149–157

    CAS  PubMed  Google Scholar 

  26. 26.

    Rajendran P, Kidane AI, Yu T-W, Dashwood W-M, Bisson WH, Löhr CV et al (2013) HDAC turnover, CtIP acetylation and dysregulated DNA damage signaling in colon cancer cells treated with sulforaphane and related dietary isothiocyanates. Epigenetics 8:612–623

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Myzak MC, Hardin K, Wang R, Dashwood RH, Ho E (2005) Sulforaphane inhibits histone deacetylase activity in BPH-1, LnCaP and PC-3 prostate epithelial cells. Carcinogenesis 27:811–819

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    Wong CP, Hsu A, Buchanan A, Palomera-Sanchez Z, Beaver LM, Houseman EA et al (2014) Effects of sulforaphane and 3,3′-diindolylmethane on genome-wide promoter methylation in normal prostate epithelial cells and prostate cancer cells. PLoS ONE 9:e86787

    PubMed  PubMed Central  Google Scholar 

  29. 29.

    Mitsiogianni M, Mantso T, Trafalis DT, Rupasinghe HPV, Zoumpourlis V, Franco R et al (2019) Allyl isothiocyanate regulates lysine acetylation and methylation marks in an experimental model of malignant melanoma. Eur J Nutr. ahead of print)

    Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Yuanfeng W, Gongnian X, Jianwei M, Shiwang L, Jun H, Lehe M (2015) Dietary sulforaphane inhibits histone deacetylase activity in B16 melanoma cells. J Funct Foods 18:182–189

    Google Scholar 

  31. 31.

    Huang S, Hsu M, Hsu S, Yang J, Huang W, Huang A et al (2014) Phenethyl isothiocyanate triggers apoptosis in human malignant melanoma A375. S2 cells through reactive oxygen species and the mitochondria-dependent pathways. Hum Exp Toxicol 33:270–283

    PubMed  Google Scholar 

  32. 32.

    Huang S-H, Wu L-W, Huang A-C, Yu C-C, Lien J-C, Huang Y-P et al (2012) Benzyl isothiocyanate (BITC) induces G2/M phase arrest and apoptosis in human melanoma A375. S2 cells through reactive oxygen species (ROS) and both mitochondria-dependent and death receptor-mediated multiple signaling pathways. J Agric Food Chem 60:665–675

    CAS  PubMed  Google Scholar 

  33. 33.

    Ma YS, Hsiao YT, Lin JJ, Liao CL, Lin CC, Chung JG (2017) Phenethyl isothiocyanate and benzyl isothiocyanate inhibit human melanoma A375.S2 cell migration and invasion by affecting MAPK signaling pathway in vitro. Anticancer Res 37:6223–6234

    CAS  PubMed  Google Scholar 

  34. 34.

    Mantso T, Sfakianos AP, Atkinson A, Anestopoulos I, Mitsiogianni M, Botaitis S et al (2016) Development of a novel experimental in vitro model of isothiocyanate-induced apoptosis in human malignant melanoma cells. Anticancer Res 36:6303–6309

    CAS  PubMed  Google Scholar 

  35. 35.

    Mantso T, Anestopoulos I, Lamprianidou E, Kotsianidis I, Pappa A, Panayiotidis MI (2019) Isothiocyanate-induced cell cycle arrest in a novel in vitro exposure protocol of human malignant melanoma (A375) cells. Anticancer Res 39:591–596

    CAS  PubMed  Google Scholar 

  36. 36.

    Rudolf K, Cervinka M, Rudolf E (2014) Sulforaphane-induced apoptosis involves p53 and p38 in melanoma cells. Apoptosis 19:734–747

    CAS  PubMed  Google Scholar 

  37. 37.

    Ni WY, Lu HF, Hsu SC, Hsiao YP, Liu KC, Liu JY et al (2014) Phenethyl isothiocyanate inhibits in vivo growth of subcutaneous xenograft tumors of human malignant melanoma A375.S2 cells. Vivo 28:891–894

    Google Scholar 

  38. 38.

    Ni W-Y, Hsiao Y-P, Hsu S-C, Hsueh S-C, Chang C-H, Ji B-C et al (2013) Oral administration of benzyl-isothiocyanate inhibits in vivo growth of subcutaneous xenograft tumors of human malignant melanoma A375. S2 cells. Vivo 27:623–626

    CAS  Google Scholar 

  39. 39.

    Thejass P, Kuttan G (2007) Modulation of cell-mediated immune response in B16F-10 melanoma-induced metastatic tumor-bearing C57BL/6 mice by sulforaphane. Immunopharmacol Immunotoxicol 29:173–186

    CAS  PubMed  Google Scholar 

  40. 40.

    Pocasap P, Weerapreeyakul N, Thumanu K (2018) Structures of isothiocyanates attributed to reactive oxygen species generation and microtubule depolymerization in HepG2 cells. Biomed Pharmacother 101:698–709

    CAS  PubMed  Google Scholar 

  41. 41.

    Crichlow GV, Fan C, Keeler C, Hodsdon M, Lolis EJ (2012) Structural interactions dictate the kinetics of macrophage migration inhibitory factor inhibition by different cancer-preventive isothiocyanates. Biochemistry 51:7506–7514

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Wang X, Di Pasqua AJ, Govind S, McCracken E, Hong C, Mi L et al (2011) Selective depletion of mutant p53 by cancer chemopreventive isothiocyanates and their structure–activity relationships. J Med Chem 54:809–816

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Nomura T, Shinoda S, Yamori T, Sawaki S, Nagata I, Ryoyama K et al (2005) Selective sensitivity to wasabi-derived 6-(methylsulfinyl)hexyl isothiocyanate of human breast cancer and melanoma cell lines studied in vitro. Cancer Detect Prev 29:155–160

    CAS  PubMed  Google Scholar 

  44. 44.

    Trachootham D, Zhou Y, Zhang H, Demizu Y, Chen Z, Pelicano H et al (2006) Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta-phenylethyl isothiocyanate. Cancer Cell 10:241–252

    CAS  PubMed  Google Scholar 

  45. 45.

    Powolny AA, Singh SV (2010) Differential response of normal (PrEC) and cancerous human prostate cells (PC-3) to phenethyl isothiocyanate-mediated changes in expression of antioxidant defense genes. Pharm Res 27:2766–2775

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Syed Alwi S-S, Cavell B-E, Donlevy A, Packham G (2012) Differential induction of apoptosis in human breast cancer cell lines by phenethyl isothiocyanate, a glutathione depleting agent. Cell Stress Chaperones 17:529–538

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Loo G (2003) Redox-sensitive mechanisms of phytochemical-mediated inhibition of cancer cell proliferation (review). J Nutr Biochem 14:64–73

    CAS  PubMed  Google Scholar 

  48. 48.

    Xu K, Thornalley P-J (2001) Involvement of glutathione metabolism in the cytotoxicity of the phenethyl isothiocyanate and its cysteine conjugate to human leukaemia cells in vitro. Biochem Pharmaco 61:165–177

    CAS  Google Scholar 

  49. 49.

    Choi S, Lew K-L, Xiao H, Herman-Antosiewicz A, Xiao D, Brown C-K et al (2007) L -Sulforaphane-induced cell death in human prostate cancer cells is regulated by inhibitor of apoptosis family proteins and Apaf-1. Carcinogenesis 28:151–162

    CAS  PubMed  Google Scholar 

  50. 50.

    Boyle GM, Martyn AC, Parsons PG (2005) Histone deacetylase inhibitors and malignant melanoma. Pigment Cell Res 18:160–166

    CAS  PubMed  Google Scholar 

  51. 51.

    Pan L, Pan H, Jiang H, Du J, Wang X, Huang B et al (2010) HDAC4 inhibits the transcriptional activation of mda-7/IL-24 induced by Sp1. Cell Mol Immunol 7:221

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Liu J, Gu J, Feng Z, Yang Y, Zhu N, Lu W et al (2016) Both HDAC5 and HDAC6 are required for the proliferation and metastasis of melanoma cells. J Transl Med 14:7

    PubMed  PubMed Central  Google Scholar 

  53. 53.

    Krumm A, Barckhausen C, Kücük P, Tomaszowski K-H, Loquai C, Fahrer J et al (2016) Enhanced histone deacetylase activity in malignant melanoma provokes RAD51 and FANCD2 triggered drug resistance. Cancer Res 76:3067–3077

    CAS  PubMed  Google Scholar 

  54. 54.

    Flørenes VA, Skrede M, Jørgensen K, Nesland JM (2004) Deacetylase inhibition in malignant melanoma: impact on cell cycle regulation and survival. Melanoma Res 14:173–181

    PubMed  Google Scholar 

  55. 55.

    Heijkants R, Willekens K, Schoonderwoerd M, Teunisse A, Nieveen M, Radaelli E et al (2017) Combined inhibition of CDK and HDAC as a promising therapeutic strategy for both cutaneous and uveal metastatic melanoma. Oncotarget 9:6174–6187

    PubMed  PubMed Central  Google Scholar 

  56. 56.

    Booth L, Roberts JL, Sander C, Lee J, Kirkwood JM, Poklepovic A et al (2017) The HDAC inhibitor AR42 interacts with pazopanib to kill trametinib/dabrafenib-resistant melanoma cells in vitro and in vivo. Oncotarget 8:16367–16386

    PubMed  PubMed Central  Google Scholar 

  57. 57.

    Gallagher SJ, Gunatilake D, Beaumont KA, Sharp DM, Tiffen JC, Heinemann A et al (2018) HDAC inhibitors restore BRAF-inhibitor sensitivity by altering PI3K and survival signalling in a subset of melanoma. Int J Cancer 142:1926–1937

    CAS  PubMed  Google Scholar 

  58. 58.

    Laino AS, Betts BC, Veerapathran A, Dolgalev I, Sarnaik A, Quayle SN et al (2019) HDAC6 selective inhibition of melanoma patient T-cells augments anti-tumor characteristics. J Immunother Cancer 7:33

    PubMed  PubMed Central  Google Scholar 

  59. 59.

    Woods DM, Sodré AL, Villagra A, Sarnaik A, Sotomayor EM, Weber J (2015) HDAC inhibition upregulates PD-1 ligands in melanoma and augments immunotherapy with PD-1 blockade. Cancer Immunol Res 3:1375–1385

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Okonkwo A, Mitra J, Johnson GS, Li L, Dashwood WM, Hegde M et al (2018) Heterocyclic analogs of sulforaphane trigger DNA damage and impede DNA repair in colon cancer cells: interplay of HATs and HDACs. Mol Nutr Food Res 62:1800228

    Google Scholar 

  61. 61.

    Abbaoui B, Telu KH, Lucas CR, Thomas-Ahner JM, Schwartz SJ, Clinton SK et al (2017) The impact of cruciferous vegetable isothiocyanates on histone acetylation and histone phosphorylation in bladder cancer. J Proteomics 156:94–103

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Boyanapalli SS, Li W, Fuentes F, Guo Y, Ramirez CN, Gonzalez X-P et al (2016) Epigenetic reactivation of RASSF1A by phenethyl isothiocyanate (PEITC) and promotion of apoptosis in LNCaP cells. Pharmacol Res 114:175–184

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Suryanarayanan V, Singh SK (2015) Assessment of dual inhibition property of newly discovered inhibitors against PCAF and GCN5 through in silico screening, molecular dynamics simulation and DFT approach. J Recept Signal Transduct 35:370–380

    CAS  Google Scholar 

  64. 64.

    Lu W, Xiong H, Chen Y, Wang C, Zhang H, Xu P et al (2018) Discovery and biological evaluation of thiobarbituric derivatives as potent p300/CBP inhibitors. Biorg Med Chem 26:5397–5407

    CAS  Google Scholar 

  65. 65.

    Bandyopadhyay D, Okan NA, Bales E, Nascimento L, Cole PA, Medrano EE (2002) Down-regulation of p300/CBP histone acetyltransferase activates a senescence checkpoint in human melanocytes. Cancer Res 62:6231–6239

    CAS  PubMed  Google Scholar 

  66. 66.

    Wang R, He Y, Robinson V, Yang Z, Hessler P, Lasko LM et al (2018) Targeting lineage-specific MITF Pathway in human melanoma cell lines by A-485, the selective small-molecule inhibitor of p300/CBP. Mol Cancer Ther 17:2543–2550

    CAS  PubMed  Google Scholar 

  67. 67.

    Yan G, Eller MS, Elm C, Larocca CA, Ryu B, Panova IP et al (2013) Selective inhibition of p300 HAT blocks cell cycle progression, induces cellular senescence, and inhibits the DNA damage response in melanoma cells. J Invest Dermatol 133:2444–2452

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Batra S, Sahu RP, Kandala PK, Srivastava SK (2010) Benzyl isothiocyanate-mediated inhibition of histone deacetylase leads to NF-κB turnoff in human pancreatic carcinoma cells. Mol Cancer Ther 9:1596–1608

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Yu C, Gong AY, Chen D, Leon DS, Young CY, Chen XM (2013) Phenethyl isothiocyanate inhibits androgen receptor-regulated transcriptional activity in prostate cancer cells through suppressing PCAF. Mol Nutr Food Res 57:1825–1833

    CAS  PubMed  Google Scholar 

  70. 70.

    Sakaguchi K, Herrera JE, Si S, Miki T, Bustin M, Vassilev A et al (1998) DNA damage activates p53 through a phosphorylation–acetylation cascade. Genes Dev 12:2831–2841

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Liu L, Scolnick DM, Trievel RC, Zhang HB, Marmorstein R, Halazonetis TD et al (1999) p53 sites acetylated in vitro by PCAF and p300 are acetylated in vivo in response to DNA damage. Mol Cell Biol 19:1202–1209

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Dekker FJ, Haisma HJ (2009) Histone acetyl transferases as emerging drug targets. Drug Discov Today 14:942–948

    CAS  PubMed  Google Scholar 

  73. 73.

    Wagner T, Jung M (2012) New lysine methyltransferase drug targets in cancer. Nat Biotechnol 30:622

    CAS  PubMed  Google Scholar 

  74. 74.

    Liu X, Wang D, Zhao Y, Tu B, Zheng Z, Wang L et al (2011) Methyltransferase Set7/9 regulates p53 activity by interacting with Sirtuin 1. Proc Natl Acad Sci USA 108:1925–1930

    CAS  PubMed  Google Scholar 

  75. 75.

    Kurash JK, Lei H, Shen Q, Marston WL, Granda BW, Fan H et al (2008) Methylation of p53 by Set7/9 mediates p53 acetylation and activity in vivo. Mol Cell 29:392–400

    CAS  PubMed  Google Scholar 

  76. 76.

    Takemoto Y, Ito A, Niwa H, Okamura M, Fujiwara T, Hirano T et al (2016) Identification of cyproheptadine as an inhibitor of SET domain containing lysine methyltransferase 7/9 (Set7/9) that regulates estrogen-dependent transcription. J Med Chem 59:3650–3660

    CAS  PubMed  Google Scholar 

  77. 77.

    Gu Y, Wang X, Liu H, Li G, Yu W, Ma Q (2018) SET7/9 promotes hepatocellular carcinoma progression through regulation of E2F1. Oncol Rep 40:1863–1874

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Gu Y, Wang Y, Wang X, Gao L, Yu W, Dong W-F (2017) Opposite effects of SET7/9 on apoptosis of human acute myeloid leukemia cells and lung cancer cells. J Cancer 8:2069–2078

    PubMed  PubMed Central  Google Scholar 

  79. 79.

    Song Y, Zhang J, Tian T, Fu X, Wang W, Li S et al (2016) SET7/9 inhibits oncogenic activities through regulation of Gli-1 expression in breast cancer. Tumor Biol 37:9311–9322

    CAS  Google Scholar 

  80. 80.

    Akiyama Y, Koda Y, Byeon S-j, Shimada S, Nishikawaji T, Sakamoto A et al (2016) Reduced expression of SET7/9, a histone mono-methyltransferase, is associated with gastric cancer progression. Oncotarget 7:3966

    PubMed  Google Scholar 

  81. 81.

    Shi X, Guo Z, Wang X, Liu X, Shi G (2015) SET8 expression is associated with overall survival in gastric cancer. Genet Mol Res 14:15609–15615

    CAS  PubMed  Google Scholar 

  82. 82.

    Yao L, Li Y, Du F, Han X, Li X, Niu Y et al (2014) Histone H4 Lys 20 methyltransferase SET8 promotes androgen receptor-mediated transcription activation in prostate cancer. Biochem Biophys Res Commun 450:692–696

    CAS  PubMed  Google Scholar 

  83. 83.

    Yang F, Sun L, Li Q, Han X, Lei L, Zhang H et al (2012) SET8 promotes epithelial–mesenchymal transition and confers TWIST dual transcriptional activities. EMBO J 31:110–123

    CAS  PubMed  Google Scholar 

  84. 84.

    Davis LE, Byrum SD, Mackintosh SG, Shalin S, Tackett AJ (2017) Identification of misregulated histone post translational modifications in melanoma. FASEB J 31:lb62

    Google Scholar 

  85. 85.

    He J, Kallin EM, Tsukada Y-i, Zhang Y (2008) The H3K36 demethylase Jhdm1b/Kdm2b regulates cell proliferation and senescence through p15Ink4b. Nat Struct Mol Biol 15:1169–1175

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Fuentes F, Paredes-Gonzalez X, Kong A-NT (2015) Dietary glucosinolates sulforaphane, phenethyl isothiocyanate, indole-3-carbinol/3,3′-diindolylmethane: anti-oxidative stress/inflammation, Nrf2, epigenetics/epigenomics and in vivo cancer chemopreventive efficacy. Curr Pharmacol Rep 1:179–196

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Varier RA, Timmers HTM (2011) Histone lysine methylation and demethylation pathways in cancer. Biochim Biophys Acta 1815:75–89

    CAS  PubMed  Google Scholar 

  88. 88.

    Elsheikh SE, Green AR, Rakha EA, Powe DG, Ahmed RA, Collins HM et al (2009) Global histone modifications in breast cancer correlate with tumor phenotypes, prognostic factors, and patient outcome. Cancer Res 69:3802–3809

    CAS  PubMed  Google Scholar 

  89. 89.

    Manuyakorn A, Paulus R, Farrell J, Dawson NA, Tze S, Cheung-Lau G et al (2010) Cellular histone modification patterns predict prognosis and treatment response in resectable pancreatic adenocarcinoma: results from RTOG 9704. J Clin Oncol 28:1358–1365

    CAS  PubMed  PubMed Central  Google Scholar 

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This work was supported by (1) start-up funds (MIP) including a Ph.D. studentship (MM) provided by the Multi-Disciplinary Research Theme in “Bio-economy” of Northumbria University; (2) an LLP Erasmus Program (AP) and (3) an “OPENSCREEN-GR: An Open-Access Research Infrastructure of Target-Based Screening Technologies and Chemical Biology for Human & Animal Health, Agriculture & Environment (MIS 5002691)” implemented under the action “Reinforcement of the Research and Innovation Infrastructure” funded by the Operational Program “Competitiveness, Entrepreneurship and Innovation (NSRF 2014–2020)” co-financed by Greece and the European Union (under the European Regional Development Fund) (AP).

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Correspondence to Mihalis I. Panayiotidis.

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Mitsiogianni, M., Trafalis, D.T., Franco, R. et al. Sulforaphane and iberin are potent epigenetic modulators of histone acetylation and methylation in malignant melanoma. Eur J Nutr 60, 147–158 (2021).

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  • Isothiocyanates
  • Sulforaphane
  • Iberin
  • Melanoma
  • Epigenetics
  • Acetyl transferases
  • Deacetylases
  • Methyl transferases
  • Lysine methylation
  • Lysine acetylation