Current perspective on the regulation of FOXO4 and its role in disease progression

  • Wen Liu
  • Yong Li
  • Bing LuoEmail author


Forkhead box O4 (FOXO4) is a member of the FOXO family that regulates a number of genes involved in metabolism, cell cycle, apoptosis, and cellular homeostasis via transcriptional activity. It also mediates cell responses to oxidative stress and treatment with antitumor agents. The expression of FOXO4 is repressed by microRNAs in multiple cancer cells, while FOXO4 function is regulated by post-translational modifications and interaction with other proteins. The deregulation of FOXO4 is closely linked to the progression of several types of cancer, senescence, and other diseases. In this review, we present recent findings on the regulation of FOXO4 in physiological and pathological conditions and provide an overview of the complex role of FOXO4 in disease development and response to therapy.


FOXO4 Cell proliferation Apoptosis Cancer Drug response 



Forkhead box


Forkhead box O




c-Jun N-terminal kinase


Mixed-lineage leukemia


Forkhead winged-helix DNA-binding domain


Nuclear localization sequence


Nuclear export sequence


Transactivation domain


Chromosomal maintenance 1


Tumor necrosis factor alpha


Mammalian ste20-like kinase


AMP-activated protein kinase


Extracellular signal-regulated kinase


Nemo-like kinase


Casein kinase 1


Dual-specificity tyrosine-phosphorylated regulated kinase 1A


CREB-binding protein


Silent information regulator 1


Histone deacetylase


Murine double minute 2


S-phase kinase-associated protein 2


Ubiquitin-specific protease 7


Transportin 1


T cell factor


Nuclear factor κB


Superoxide dismutase 2


Reactive oxidative species


Growth-arrest and DNA damage-response protein 45


B cell lymphoma extra-large


B-cell lymphoma 6


Bcl-2 interacting mediator


Bcl-2 associated X protein


Smooth muscle cell


Serum response factor


Hypoxia-inducible factor 1α protein


Vascular endothelial growth factor


Muscle atrophy F-box


Muscle ring finger 1


Tumor necrosis factor


With-no-lysine kinase


Advanced glycation end product


Tumor node metastasis


Author contributions

LW and LY collected the related papers and drafted and wrote the manuscript. BL revised the manuscript. All authors read and approved the final manuscript.


This work was supported by the National Foundation of Natural Science of China (81801264), the Shandong Provincial Natural Science Foundation (ZR2017BH106), and the China Postdoctoral Science Foundation (2017M610411).

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.


  1. 1.
    Huang H, Tindall DJ (2007) Dynamic FoxO transcription factors. J Cell Sci 120:2479–2487CrossRefPubMedGoogle Scholar
  2. 2.
    Maiese K, Hou J, Chong ZZ, Shang YC (2009) A fork in the path: developing therapeutic inroads with FoxO proteins. Oxid Med Cell Longev. 2:119–129CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Monsalve M, Olmos Y (2011) The complex biology of FOXO. Curr Drug Targets 12:1322–1350CrossRefPubMedGoogle Scholar
  4. 4.
    Farhan M, Wang H, Gaur U, Little PJ, Xu J, Zheng W (2017) FOXO signaling pathways as therapeutic targets in cancer. Int J Biol Sci 13:815–827CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Tikhanovich I, Cox J, Weinman SA (2013) Forkhead box class O transcription factors in liver function and disease. J Gastroenterol Hepatol 28(Suppl 1):125–131CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Hannenhalli S, Kaestner KH (2009) The evolution of Fox genes and their role in development and disease. Nat Rev Genet 10:233–240CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Kim DH, Perdomo G, Zhang T, Slusher S, Lee S, Phillips BE, Fan Y, Giannoukakis N, Gramignoli R, Strom S, Ringquist S, Dong HH (2011) FoxO6 integrates insulin signaling with gluconeogenesis in the liver. Diabetes 60:2763–2774CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Lee TI, Young RA (2013) Transcriptional regulation and its misregulation in disease. Cell 152:1237–1251CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Myatt SS, Lam EW (2007) The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer 7:847–859CrossRefPubMedGoogle Scholar
  10. 10.
    Wang W, Zhou PH, Hu W (2016) Overexpression of FOXO4 induces apoptosis of clear-cell renal carcinoma cells through downregulation of Bim. Mol Med Rep 13:2229–2234CrossRefPubMedGoogle Scholar
  11. 11.
    Lu C, Yang Z, Jiang S, Yang Y, Han Y, Lv J, Li T, Chen F, Yu Y (2018) Forkhead box O4 transcription factor in human neoplasms: cannot afford to lose the novel suppressor. J Cell Physiol 234:8647–8658CrossRefPubMedGoogle Scholar
  12. 12.
    Jiang S, Yang Z, Di S, Hu W, Ma Z, Chen F, Yang Y (2018) Novel role of forkhead box O4 transcription factor in cancer: bringing out the good or the bad. Semin Cancer Biol 50:1–12CrossRefPubMedGoogle Scholar
  13. 13.
    Borkhardt A, Repp R, Haas OA, Leis T, Harbott J, Kreuder J, Hammermann J, Henn T, Lampert F (1997) Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23). Oncogene 14:195–202CrossRefPubMedGoogle Scholar
  14. 14.
    Biggs WH 3rd, Cavenee WK, Arden KC (2001) Identification and characterization of members of the FKHR (FOX O) subclass of winged-helix transcription factors in the mouse. Mamm Genome 12:416–425CrossRefPubMedGoogle Scholar
  15. 15.
    Lin K, Hsin H, Libina N, Kenyon C (2001) Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nat Genet 28:139–145CrossRefPubMedGoogle Scholar
  16. 16.
    Macara IG (1999) Nuclear transport: randy couples. Curr Biol 9:R436–R439CrossRefPubMedGoogle Scholar
  17. 17.
    Brownawell AM, Kops GJ, Macara IG, Burgering BM (2001) Inhibition of nuclear import by protein kinase B (Akt) regulates the subcellular distribution and activity of the forkhead transcription factor AFX. Mol Cell Biol 21:3534–3546CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Baar MP, Brandt RMC, Putavet DA, Klein JDD, Derks KWJ, Bourgeois BRM, Stryeck S, Rijksen Y, van Willigenburg H, Feijtel DA, van der Pluijm I, Essers J, van Cappellen WA, van IJcken WF, Houtsmuller AB, Pothof J, de Bruin RWF, Madl T, Hoeijmakers JHJ, Campisi J, de Keizer PLJ (2017) Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell 169(132–147):e16Google Scholar
  19. 19.
    Bourgeois B, Madl T (2018) Regulation of cellular senescence via the FOXO4-p53 axis. FEBS Lett 592:2083–2097CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Wang F, Marshall CB, Yamamoto K, Li GY, Plevin MJ, You H, Mak TW, Ikura M (2008) Biochemical and structural characterization of an intramolecular interaction in FOXO3a and its binding with p53. J Mol Biol 384:590–603CrossRefPubMedGoogle Scholar
  21. 21.
    Nowak K, Killmer K, Gessner C, Lutz W (2007) E2F-1 regulates expression of FOXO1 and FOXO3a. Biochim Biophys Acta 1769:244–252CrossRefPubMedGoogle Scholar
  22. 22.
    Berry FB, Skarie JM, Mirzayans F, Fortin Y, Hudson TJ, Raymond V, Link BA, Walter MA (2008) FOXC1 is required for cell viability and resistance to oxidative stress in the eye through the transcriptional regulation of FOXO1A. Hum Mol Genet 17:490–505CrossRefPubMedGoogle Scholar
  23. 23.
    Essaghir A, Dif N, Marbehant CY, Coffer PJ, Demoulin JB (2009) The transcription of FOXO genes is stimulated by FOXO3 and repressed by growth factors. J Biol Chem 284:10334–10342CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Franz F, Weidinger C, Krause K, Gimm O, Dralle H, Fuhrer D (2016) The transcriptional regulation of FOXO genes in thyrocytes. Horm Metab Res 48:601–606CrossRefPubMedGoogle Scholar
  25. 25.
    Mofarrahi M, Guo Y, Haspel JA, Choi AM, Davis EC, Gouspillou G, Hepple RT, Godin R, Burelle Y, Hussain SN (2013) Autophagic flux and oxidative capacity of skeletal muscles during acute starvation. Autophagy. 9:1604–1620CrossRefPubMedGoogle Scholar
  26. 26.
    Furuyama T, Yamashita H, Kitayama K, Higami Y, Shimokawa I, Mori N (2002) Effects of aging and caloric restriction on the gene expression of Foxo 1, 3, and 4 (FKHR, FKHRL1, and AFX) in the rat skeletal muscles. Microsc Res Tech 59:331–334CrossRefPubMedGoogle Scholar
  27. 27.
    Li Q, Huang H, He Z, Sun Y, Tang Y, Shang X, Wang C (2018) Regulatory effects of antitumor agent matrine on FOXO and PI3K-AKT pathway in castration-resistant prostate cancer cells. Sci China Life Sci 61:550–558CrossRefPubMedGoogle Scholar
  28. 28.
    Zhang J, Guo W, Tian B, Sun M, Li H, Zhou L, Liu X (2015) Puerarin attenuates cognitive dysfunction and oxidative stress in vascular dementia rats induced by chronic ischemia. Int J Clin Exp Pathol 8:4695–4704PubMedPubMedCentralGoogle Scholar
  29. 29.
    Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Friedlander MR, Lizano E, Houben AJ, Bezdan D, Banez-Coronel M, Kudla G, Mateu-Huertas E, Kagerbauer B, Gonzalez J, Chen KC, LeProust EM, Marti E, Estivill X (2014) Evidence for the biogenesis of more than 1,000 novel human microRNAs. Genome Biol 15:R57CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Friedman RC, Farh KK, Burge CB, Bartel DP (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19:92–105CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Zhang J, Wu L, Chen J, Lin S, Cai D, Chen C, Chen Z (2018) Downregulation of MicroRNA 29a/b exacerbated diabetic retinopathy by impairing the function of Muller cells via Forkhead box protein O4. Diab Vasc Dis Res 15:214–222CrossRefPubMedGoogle Scholar
  33. 33.
    Chen L, Tang Y, Wang J, Yan Z, Xu R (2013) miR-421 induces cell proliferation and apoptosis resistance in human nasopharyngeal carcinoma via downregulation of FOXO4. Biochem Biophys Res Commun 435:745–750CrossRefPubMedGoogle Scholar
  34. 34.
    Liu X, Zhang Z, Sun L, Chai N, Tang S, Jin J, Hu H, Nie Y, Wang X, Wu K, Jin H, Fan D (2011) MicroRNA-499-5p promotes cellular invasion and tumor metastasis in colorectal cancer by targeting FOXO4 and PDCD4. Carcinogenesis 32:1798–1805CrossRefPubMedGoogle Scholar
  35. 35.
    Wang GJ, Liu GH, Ye YW, Fu Y, Zhang XF (2015) The role of microRNA-1274a in the tumorigenesis of gastric cancer: accelerating cancer cell proliferation and migration via directly targeting FOXO4. Biochem Biophys Res Commun 459:629–635CrossRefPubMedGoogle Scholar
  36. 36.
    Chen B, Bao Y, Chen X, Yi J, Liu S, Fang Z, Zheng S, Chen J (2015) Mir-664 promotes osteosarcoma cells proliferation via downregulating of FOXO4. Biomed Pharmacother 75:1–7CrossRefPubMedGoogle Scholar
  37. 37.
    Li J, Hu L, Tian C, Lu F, Wu J, Liu L (2015) microRNA-150 promotes cervical cancer cell growth and survival by targeting FOXO4. BMC Mol Biol 16:24CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Li H, Ouyang R, Wang Z, Zhou W, Chen H, Jiang Y, Zhang Y, Li H, Liao M, Wang W, Ye M, Ding Z, Feng X, Liu J, Zhang B (2016) MiR-150 promotes cellular metastasis in non-small cell lung cancer by targeting FOXO4. Sci Rep 6:39001CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Shang L, Quan A, Sun H, Xu Y, Sun G, Cao P (2019) MicroRNA-148a-3p promotes survival and migration of endothelial cells isolated from Apoe deficient mice through restricting circular RNA 0003575. Gene 711:143948CrossRefPubMedGoogle Scholar
  40. 40.
    Chen C, Tan H, Bi J, Li L, Rong T, Lin Y, Sun P, Liang J, Jiao Y, Li Z, Sun L, Shen J (2019) LncRNA-SULT1C2A regulates Foxo4 in congenital scoliosis by targeting rno-miR-466c-5p through PI3K-ATK signalling. J Cell Mol Med 23:4582–4591PubMedPubMedCentralGoogle Scholar
  41. 41.
    Liu X, Ma BD, Liu S, Liu J, Ma BX (2019) Long noncoding RNA LINC00341 promotes the vascular smooth muscle cells proliferation and migration via miR-214/FOXO4 feedback loop. Am J Transl Res 11:1835–1842PubMedPubMedCentralGoogle Scholar
  42. 42.
    Wu YX, Zhang SH, Cui J, Liu FT (2018) Long noncoding RNA XR007793 regulates proliferation and migration of vascular smooth muscle cell via suppressing miR-23b. Med Sci Monit 24:5895–5903CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Yu C, Chen DQ, Liu HX, Li WB, Lu JW, Feng JF (2019) Rosmarinic acid reduces the resistance of gastric carcinoma cells to 5-fluorouracil by downregulating FOXO4-targeting miR-6785-5p. Biomed Pharmacother 109:2327–2334CrossRefPubMedGoogle Scholar
  44. 44.
    Bian L, Zhi X, Ma L, Zhang J, Chen P, Sun S, Li J, Sun Y, Qin J (2018) Hsa_circRNA_103809 regulated the cell proliferation and migration in colorectal cancer via miR-532-3p/FOXO4 axis. Biochem Biophys Res Commun 505:346–352CrossRefPubMedGoogle Scholar
  45. 45.
    Essers MA, Weijzen S, de Vries-Smits AM, Saarloos I, de Ruiter ND, Bos JL, Burgering BM (2004) FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO J 23:4802–4812CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    de Keizer PL, Packer LM, Szypowska AA, Riedl-Polderman PE, van den Broek NJ, de Bruin A, Dansen TB, Marais R, Brenkman AB, Burgering BM (2010) Activation of forkhead box O transcription factors by oncogenic BRAF promotes p21cip1-dependent senescence. Cancer Res 70:8526–8536CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    De Ruiter ND, Burgering BM, Bos JL (2001) Regulation of the Forkhead transcription factor AFX by Ral-dependent phosphorylation of threonines 447 and 451. Mol Cell Biol 21:8225–8235CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Wang Y, Zhou Y, Graves DT (2014) FOXO transcription factors: their clinical significance and regulation. Biomed Res Int 2014:925350PubMedPubMedCentralGoogle Scholar
  49. 49.
    Rajendran NK, Dhilip Kumar SS, Houreld NN, Abrahamse H (2018) Understanding the perspectives of forkhead transcription factors in delayed wound healing. J Cell Commun Signal 13:151–162CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Szypowska AA, de Ruiter H, Meijer LA, Smits LM, Burgering BM (2011) Oxidative stress-dependent regulation of Forkhead box O4 activity by nemo-like kinase. Antioxid Redox Signal 14:563–578CrossRefPubMedGoogle Scholar
  51. 51.
    Woods YL, Rena G, Morrice N, Barthel A, Becker W, Guo S, Unterman TG, Cohen P (2001) The kinase DYRK1A phosphorylates the transcription factor FKHR at Ser329 in vitro, a novel in vivo phosphorylation site. Biochem J 355:597–607CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Rena G, Woods YL, Prescott AR, Peggie M, Unterman TG, Williams MR, Cohen P (2002) Two novel phosphorylation sites on FKHR that are critical for its nuclear exclusion. EMBO J 21:2263–2271CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY, Hu LS, Cheng HL, Jedrychowski MP, Gygi SP, Sinclair DA, Alt FW, Greenberg ME (2004) Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303:2011–2015CrossRefPubMedGoogle Scholar
  54. 54.
    Fukuoka M, Daitoku H, Hatta M, Matsuzaki H, Umemura S, Fukamizu A (2003) Negative regulation of forkhead transcription factor AFX (Foxo4) by CBP-induced acetylation. Int J Mol Med 12:503–508PubMedGoogle Scholar
  55. 55.
    Mahmud DL, G-Amlak M, Deb DK, Platanias LC, Uddin S, Wickrema A (2002) Phosphorylation of forkhead transcription factors by erythropoietin and stem cell factor prevents acetylation and their interaction with coactivator p300 in erythroid progenitor cells. Oncogene 21:1556–1562CrossRefPubMedGoogle Scholar
  56. 56.
    Dansen TB, Smits LM, van Triest MH, de Keizer PL, van Leenen D, Koerkamp MG, Szypowska A, Meppelink A, Brenkman AB, Yodoi J, Holstege FC, Burgering BM (2009) Redox-sensitive cysteines bridge p300/CBP-mediated acetylation and FoxO4 activity. Nat Chem Biol 5:664–672CrossRefPubMedGoogle Scholar
  57. 57.
    van der Horst A, Tertoolen LG, de Vries-Smits LM, Frye RA, Medema RH, Burgering BM (2004) FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). J Biol Chem 279:28873–28879CrossRefPubMedGoogle Scholar
  58. 58.
    Huang H, Tindall DJ (2011) Regulation of FOXO protein stability via ubiquitination and proteasome degradation. Biochim Biophys Acta 1813:1961–1964CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    van der Horst A, de Vries-Smits AM, Brenkman AB, van Triest MH, van den Broek N, Colland F, Maurice MM, Burgering BM (2006) FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP. Nat Cell Biol 8:1064–1073CrossRefPubMedGoogle Scholar
  60. 60.
    Brenkman AB, de Keizer PL, van den Broek NJ, Jochemsen AG, Burgering BM (2008) Mdm2 induces mono-ubiquitination of FOXO4. PLoS One 3:e2819CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Huang H, Regan KM, Wang F, Wang D, Smith DI, van Deursen JM, Tindall DJ (2005) Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation. Proc Natl Acad Sci USA 102:1649–1654CrossRefPubMedGoogle Scholar
  62. 62.
    Calnan DR, Brunet A (2008) The FoxO code. Oncogene 27:2276–2288CrossRefPubMedGoogle Scholar
  63. 63.
    Putker M, Madl T, Vos HR, de Ruiter H, Visscher M, van den Berg MC, Kaplan M, Korswagen HC, Boelens R, Vermeulen M, Burgering BM, Dansen TB (2013) Redox-dependent control of FOXO/DAF-16 by transportin-1. Mol Cell 49:730–742CrossRefPubMedGoogle Scholar
  64. 64.
    Essers MA, de Vries-Smits LM, Barker N, Polderman PE, Burgering BM, Korswagen HC (2005) Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science 308:1181–1184CrossRefPubMedGoogle Scholar
  65. 65.
    Brenkman AB, de Keizer PL, van den Broek NJ, van der Groep P, van Diest PJ, van der Horst A, Smits AM, Burgering BM (2008) The peptidyl-isomerase Pin1 regulates p27kip1 expression through inhibition of Forkhead box O tumor suppressors. Cancer Res 68:7597–7605CrossRefPubMedGoogle Scholar
  66. 66.
    Brenkman AB, van den Broek NJ, de Keizer PL, van Gent DC, Burgering BM (2010) The DNA damage repair protein Ku70 interacts with FOXO4 to coordinate a conserved cellular stress response. FASEB J 24:4271–4280CrossRefPubMedGoogle Scholar
  67. 67.
    Medema RH, Kops GJ, Bos JL, Burgering BM (2000) AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404:782–787CrossRefPubMedGoogle Scholar
  68. 68.
    Rodier F, Munoz DP, Teachenor R, Chu V, Le O, Bhaumik D, Coppe JP, Campeau E, Beausejour CM, Kim SH, Davalos AR, Campisi J (2011) DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion. J Cell Sci 124:68–81CrossRefPubMedGoogle Scholar
  69. 69.
    Zhou W, Cao Q, Peng Y, Zhang QJ, Castrillon DH, DePinho RA, Liu ZP (2009) FoxO4 inhibits NF-kappaB and protects mice against colonic injury and inflammation. Gastroenterology 137:1403–1414CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Hosaka T, Biggs WH 3rd, Tieu D, Boyer AD, Varki NM, Cavenee WK, Arden KC (2004) Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. Proc Natl Acad Sci USA 101:2975–2980CrossRefPubMedGoogle Scholar
  71. 71.
    Paik JH, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z, Miao L, Tothova Z, Horner JW, Carrasco DR, Jiang S, Gilliland DG, Chin L, Wong WH, Castrillon DH, DePinho RA (2007) FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 128:309–323CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Araujo J, Breuer P, Dieringer S, Krauss S, Dorn S, Zimmermann K, Pfeifer A, Klockgether T, Wuellner U, Evert BO (2011) FOXO4-dependent upregulation of superoxide dismutase-2 in response to oxidative stress is impaired in spinocerebellar ataxia type 3. Hum Mol Genet 20:2928–2941CrossRefPubMedGoogle Scholar
  73. 73.
    Putker M, Vos HR, Dansen TB (2014) Intermolecular disulfide-dependent redox signalling. Biochem Soc Trans 42:971–978CrossRefPubMedGoogle Scholar
  74. 74.
    Kops GJ, Medema RH, Glassford J, Essers MA, Dijkers PF, Coffer PJ, Lam EW, Burgering BM (2002) Control of cell cycle exit and entry by protein kinase B-regulated forkhead transcription factors. Mol Cell Biol 22:2025–2036CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Schmidt M, Fernandez de Mattos S, van der Horst A, Klompmaker R, Kops GJ, Lam EW, Burgering BM, Medema RH (2002) Cell cycle inhibition by FoxO forkhead transcription factors involves downregulation of cyclin D. Mol Cell Biol 22:7842–7852CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Furukawa-Hibi Y, Yoshida-Araki K, Ohta T, Ikeda K, Motoyama N (2002) FOXO forkhead transcription factors induce G(2)-M checkpoint in response to oxidative stress. J Biol Chem 277:26729–26732CrossRefPubMedGoogle Scholar
  77. 77.
    Zhang X, Tang N, Hadden TJ, Rishi AK (2011) Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta 1813:1978–1986CrossRefPubMedGoogle Scholar
  78. 78.
    Finucane DM, Bossy-Wetzel E, Waterhouse NJ, Cotter TG, Green DR (1999) Bax-induced caspase activation and apoptosis via cytochrome c release from mitochondria is inhibitable by Bcl-xL. J Biol Chem 274:2225–2233CrossRefPubMedGoogle Scholar
  79. 79.
    Tang TT, Dowbenko D, Jackson A, Toney L, Lewin DA, Dent AL, Lasky LA (2002) The forkhead transcription factor AFX activates apoptosis by induction of the BCL-6 transcriptional repressor. J Biol Chem 277:14255–14265CrossRefPubMedGoogle Scholar
  80. 80.
    Yu L, Zhang W, Huang C, Liang Q, Bao H, Gong Z, Xu M, Wang Z, Wen M, Cheng X (2018) FoxO4 promotes myocardial ischemia-reperfusion injury: the role of oxidative stress-induced apoptosis. Am J Transl Res 10:2890–2900PubMedPubMedCentralGoogle Scholar
  81. 81.
    Liu ZP, Wang Z, Yanagisawa H, Olson EN (2005) Phenotypic modulation of smooth muscle cells through interaction of Foxo4 and myocardin. Dev Cell 9:261–270CrossRefPubMedGoogle Scholar
  82. 82.
    Jin Y, Xie Y, Ostriker AC, Zhang X, Liu R, Lee MY, Leslie KL, Tang W, Du J, Lee SH, Wang Y, Sessa WC, Hwa J, Yu J, Martin KA (2017) Opposing actions of AKT (protein kinase B) isoforms in vascular smooth muscle injury and therapeutic response. Arterioscler Thromb Vasc Biol 37:2311–2321CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Hayashi K, Saga H, Chimori Y, Kimura K, Yamanaka Y, Sobue K (1998) Differentiated phenotype of smooth muscle cells depends on signaling pathways through insulin-like growth factors and phosphatidylinositol 3-kinase. J Biol Chem 273:28860–28867CrossRefPubMedGoogle Scholar
  84. 84.
    Zhao G, Fu Y, Cai Z, Yu F, Gong Z, Dai R, Hu Y, Zeng L, Xu Q, Kong W (2017) Unspliced XBP1 confers VSMC homeostasis and prevents aortic aneurysm formation via FoxO4 interaction. Circ Res 121:1331–1345CrossRefPubMedGoogle Scholar
  85. 85.
    Li H, Liang J, Castrillon DH, DePinho RA, Olson EN, Liu ZP (2007) FoxO4 regulates tumor necrosis factor alpha-directed smooth muscle cell migration by activating matrix metalloproteinase 9 gene transcription. Mol Cell Biol 27:2676–2686CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Shi X, Wallis AM, Gerard RD, Voelker KA, Grange RW, DePinho RA, Garry MG, Garry DJ (2012) Foxk1 promotes cell proliferation and represses myogenic differentiation by regulating Foxo4 and Mef2. J Cell Sci 125:5329–5337CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Ryu KJ, Park C, Hong M, Ko YH, Kim WS, Kim SJ (2017) FOXO4 expression is related to stem cell-like properties and resistance to treatment in diffuse large B-cell lymphoma. Oncotarget 8:2466–2476PubMedGoogle Scholar
  88. 88.
    Storz P (2011) Forkhead homeobox type O transcription factors in the responses to oxidative stress. Antioxid Redox Signal 14:593–605CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    van Doeselaar S, Burgering BMT (2018) FOXOs maintaining the equilibrium for better or for worse. Curr Top Dev Biol 127:49–103CrossRefPubMedGoogle Scholar
  90. 90.
    Tang TT, Lasky LA (2003) The forkhead transcription factor FOXO4 induces the down-regulation of hypoxia-inducible factor 1 alpha by a von Hippel-Lindau protein-independent mechanism. J Biol Chem 278:30125–30135CrossRefPubMedGoogle Scholar
  91. 91.
    Nakayoshi T, Sasaki K, Kajimoto H, Koiwaya H, Ohtsuka M, Ueno T, Chibana H, Itaya N, Sasaki M, Yokoyama S, Fukumoto Y, Imaizumi T (2014) FOXO4-knockdown suppresses oxidative stress-induced apoptosis of early pro-angiogenic cells and augments their neovascularization capacities in ischemic limbs. PLoS One 9:e92626CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Furuyama T, Kitayama K, Shimoda Y, Ogawa M, Sone K, Yoshida-Araki K, Hisatsune H, Nishikawa S, Nakayama K, Nakayama K, Ikeda K, Motoyama N, Mori N (2004) Abnormal angiogenesis in Foxo1 (Fkhr)-deficient mice. J Biol Chem 279:34741–34749CrossRefPubMedGoogle Scholar
  93. 93.
    Hornsveld M, Dansen TB, Derksen PW, Burgering BMT (2018) Re-evaluating the role of FOXOs in cancer. Semin Cancer Biol 50:90–100CrossRefPubMedGoogle Scholar
  94. 94.
    Martins R, Lithgow GJ, Link W (2016) Long live FOXO: unraveling the role of FOXO proteins in aging and longevity. Aging Cell 15:196–207CrossRefPubMedGoogle Scholar
  95. 95.
    Zhu X, Zheng X, Wu Y (2014) Cleaved high molecular weight kininogen stimulates JNK/FOXO4/MnSOD pathway for induction of endothelial progenitor cell senescence. Biochem Biophys Res Commun 450:1261–1265CrossRefPubMedGoogle Scholar
  96. 96.
    van Willigenburg H, de Keizer PLJ, de Bruin RWF (2018) Cellular senescence as a therapeutic target to improve renal transplantation outcome. Pharmacol Res 130:322–330CrossRefPubMedGoogle Scholar
  97. 97.
    Qi XF, Chen ZY, Xia JB, Zheng L, Zhao H, Pi LQ, Park KS, Kim SK, Lee KJ, Cai DQ (2015) FoxO3a suppresses the senescence of cardiac microvascular endothelial cells by regulating the ROS-mediated cell cycle. J Mol Cell Cardiol 81:114–126CrossRefPubMedGoogle Scholar
  98. 98.
    Li M, Chiu JF, Mossman BT, Fukagawa NK (2006) Down-regulation of manganese-superoxide dismutase through phosphorylation of FOXO3a by Akt in explanted vascular smooth muscle cells from old rats. J Biol Chem 281:40429–40439CrossRefPubMedGoogle Scholar
  99. 99.
    Edstrom E, Altun M, Hagglund M, Ulfhake B (2006) Atrogin-1/MAFbx and MuRF1 are downregulated in aging-related loss of skeletal muscle. J Gerontol A Biol Sci Med Sci 61:663–674CrossRefPubMedGoogle Scholar
  100. 100.
    Moylan JS, Smith JD, Chambers MA, McLoughlin TJ, Reid MB (2008) TNF induction of atrogin-1/MAFbx mRNA depends on Foxo4 expression but not AKT-Foxo1/3 signaling. Am J Physiol Cell Physiol 295:C986–C993CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Zhang Y, Tessier SN, Storey KB (2016) Inhibition of skeletal muscle atrophy during torpor in ground squirrels occurs through downregulation of MyoG and inactivation of Foxo4. Cryobiology 73:112–119CrossRefPubMedGoogle Scholar
  102. 102.
    Mandai S, Mori T, Nomura N, Furusho T, Arai Y, Kikuchi H, Sasaki E, Sohara E, Rai T, Uchida S (2018) WNK1 regulates skeletal muscle cell hypertrophy by modulating the nuclear localization and transcriptional activity of FOXO4. Sci Rep 8:9101CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Imae M, Fu Z, Yoshida A, Noguchi T, Kato H (2003) Nutritional and hormonal factors control the gene expression of FoxOs, the mammalian homologues of DAF-16. J Mol Endocrinol 30:253–262CrossRefPubMedGoogle Scholar
  104. 104.
    Chuang PY, Dai Y, Liu R, He H, Kretzler M, Jim B, Cohen CD, He JC (2011) Alteration of forkhead box O (foxo4) acetylation mediates apoptosis of podocytes in diabetes mellitus. PLoS One 6:e23566CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Nakatani Y, Inagi R (2016) Epigenetic regulation through SIRT1 in podocytes. Curr Hypertens Rev 12:89–94CrossRefPubMedGoogle Scholar
  106. 106.
    Xiong X, Tao R, DePinho RA, Dong XC (2013) Deletion of hepatic FoxO1/3/4 genes in mice significantly impacts on glucose metabolism through downregulation of gluconeogenesis and upregulation of glycolysis. PLoS One 8:e74340CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Haeusler RA, Hartil K, Vaitheesvaran B, Arrieta-Cruz I, Knight CM, Cook JR, Kammoun HL, Febbraio MA, Gutierrez-Juarez R, Kurland IJ, Accili D (2014) Integrated control of hepatic lipogenesis versus glucose production requires FoxO transcription factors. Nat Commun 5:5190CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Kim-Muller JY, Zhao S, Srivastava S, Mugabo Y, Noh HL, Kim YR, Madiraju SR, Ferrante AW, Skolnik EY, Prentki M, Accili D (2014) Metabolic inflexibility impairs insulin secretion and results in MODY-like diabetes in triple FoxO-deficient mice. Cell Metab 20:593–602CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Takaishi H, Konishi H, Matsuzaki H, Ono Y, Shirai Y, Saito N, Kitamura T, Ogawa W, Kasuga M, Kikkawa U, Nishizuka Y (1999) Regulation of nuclear translocation of forkhead transcription factor AFX by protein kinase B. Proc Natl Acad Sci USA 96:11836–11841CrossRefPubMedGoogle Scholar
  110. 110.
    Roy SK, Srivastava RK, Shankar S (2010) Inhibition of PI3K/AKT and MAPK/ERK pathways causes activation of FOXO transcription factor, leading to cell cycle arrest and apoptosis in pancreatic cancer. J Mol Signal 5:10CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Wang J, Yuan L, Xiao H, Wang C, Xiao C, Wang Y, Liu X (2014) A novel mechanism for momordin Ic-induced HepG2 apoptosis: involvement of PI3K- and MAPK-dependent PPARgamma activation. Food Funct 5:859–868CrossRefPubMedGoogle Scholar
  112. 112.
    Yuan L, Wang J, Xiao H, Xiao C, Wang Y, Liu X (2012) Isoorientin induces apoptosis through mitochondrial dysfunction and inhibition of PI3K/Akt signaling pathway in HepG2 cancer cells. Toxicol Appl Pharmacol 265:83–92CrossRefPubMedGoogle Scholar
  113. 113.
    Sheng Z, Ma L, Sun JE, Zhu LJ, Green MR (2011) BCR-ABL suppresses autophagy through ATF5-mediated regulation of mTOR transcription. Blood 118:2840–2848CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Liou AT, Chen MF, Yang CW (2017) Curcumin induces p53-null hepatoma cell line Hep3B apoptosis through the AKT-PTEN-FOXO4 pathway. Evid Based Complement Alternat Med 2017:4063865PubMedPubMedCentralGoogle Scholar
  115. 115.
    Chen Q, Ganapathy S, Singh KP, Shankar S, Srivastava RK (2010) Resveratrol induces growth arrest and apoptosis through activation of FOXO transcription factors in prostate cancer cells. PLoS One 5:e15288CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Hori YS, Kuno A, Hosoda R, Horio Y (2013) Regulation of FOXOs and p53 by SIRT1 modulators under oxidative stress. PLoS One 8:e73875CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Lupertz R, Chovolou Y, Unfried K, Kampkotter A, Watjen W, Kahl R (2008) The forkhead transcription factor FOXO4 sensitizes cancer cells to doxorubicin-mediated cytotoxicity. Carcinogenesis 29:2045–2052CrossRefPubMedGoogle Scholar
  118. 118.
    Link W, Oyarzabal J, Serelde BG, Albarran MI, Rabal O, Cebria A, Alfonso P, Fominaya J, Renner O, Peregrina S, Soilan D, Ceballos PA, Hernandez AI, Lorenzo M, Pevarello P, Granda TG, Kurz G, Carnero A, Bischoff JR (2009) Chemical interrogation of FOXO3a nuclear translocation identifies potent and selective inhibitors of phosphoinositide 3-kinases. J Biol Chem 284:28392–28400CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Zeng Z, Samudio IJ, Zhang W, Estrov Z, Pelicano H, Harris D, Frolova O, Hail N Jr, Chen W, Kornblau SM, Huang P, Lu Y, Mills GB, Andreeff M, Konopleva M (2006) Simultaneous inhibition of PDK1/AKT and Fms-like tyrosine kinase 3 signaling by a small-molecule KP372-1 induces mitochondrial dysfunction and apoptosis in acute myelogenous leukemia. Cancer Res 66:3737–3746CrossRefPubMedGoogle Scholar
  120. 120.
    Valis K, Prochazka L, Boura E, Chladova J, Obsil T, Rohlena J, Truksa J, Dong LF, Ralph SJ, Neuzil J (2011) Hippo/Mst1 stimulates transcription of the proapoptotic mediator NOXA in a FoxO1-dependent manner. Cancer Res 71:946–954CrossRefPubMedGoogle Scholar
  121. 121.
    Yokoyama C, Sueyoshi Y, Ema M, Mori Y, Takaishi K, Hisatomi H (2017) Induction of oxidative stress by anticancer drugs in the presence and absence of cells. Oncol Lett 14:6066–6070PubMedPubMedCentralGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Pathogenic Biology, Faculty of MedicineQingdao UniversityQingdaoChina
  2. 2.Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: PhysiologyFaculty of Medicine, Qingdao UniversityQingdaoChina

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