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Disruption of the Molecular Circadian Clock and Cancer: An Epigenetic Link

Abstract

The circadian clock is regulated at the molecular level by feedback circuits of a group of genes known as "clock genes", which establish a mechanism that controls circadian cellular physiology to maintain the balance between cell proliferation, response to DNA damage and apoptosis. Alterations in the expression of clock genes due to genetic or epigenetic mechanisms have been associated with multiple diseases including cancer. Even some clock genes such as the Per1, Per2, Bmal1 genes have been proposed as tumor suppressor genes, with a relevant role during carcinogenesis. At the molecular level, multiple mechanisms of molecular control have been described to link circadian transcription, cell cycle control, and tumorigenesis. In addition, recent findings describe an epigenetic control of circadian transcription, at the level of DNA methylation as well as in the modifications of histones. However, the link between the circadian epigenome and cancer remains unclear. In this article, we review the evidence that suggests a relationship between alterations in the expression of clock genes, with the development of cancer, from the epigenetic landscape.

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Fig. 1
Fig. 2

Figure adapted from Masri et al. (2013)

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Figure adapted from Fu et al. (2002)

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References

  1. Alam H, Gu B, Lee MG (2015) Histone methylation modifiers in cellular signaling pathways. Cell Mol Life Sci 72:4577–4592

  2. Alenghat T, Meyers K, Mullican SE, Leitner K, Adeniji-Adele A, Avila J, Bućan M, Ahima RS, Kaestner KH, Lazar MA (2008) Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology. Nature 456:997–1000

  3. Archer SY, Meng S, Shei A, Hodin R (1998) p21WAF1 is required for butyrate-mediated growth inhibition of colon cancer cells. Proc Natl Acad Sci USA 95:6791–6796

  4. Baylin SB (2005) DNA methylation and gene silencing in cancer. Nat Clin Pract Oncol 2:4–11

  5. Blask DE, Hill SM, Dauchy RT, Xiang S, Yuan L, Duplessis T, Mao L, Dauchy E, Sauer LA (2011) Circadian regulation of molecular, dietary, and metabolic signaling mechanisms of human breast cancer growth by the nocturnal melatonin signal and the consequences of its disruption by light at night. J Pineal Res 51:259–269

  6. Brandi G, Calabrese C, Pantaleo MA, Morselli Labate A, Di Febo G, Hakim R, De Vivo A, Di Marco MC, Biasco G (2004) Circadian variations of rectal cell proliferation in patients affected by advanced colorectal cancer. Cancer Lett 208:193–196

  7. 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 69:7619–7625

  8. Cash E, Sephton SE, Chagpar AB, Spiegel D, Rebholz WN, Zimmaro LA, Tillie JM, Dhabhar FS (2015) Circadian disruption and biomarkers of tumor progression in breast cancer patients awaiting surgery. Brain Behav Immun 48:102–114

  9. Chen ST, Choo KB, Hou MF, Yeh KT, Kuo SJ, Chang JG (2005) Deregulated expression of the PER1, PER2 and PER3 genes in breast cancers. Carcinogenesis 26:1241–1246

  10. Chen YJ, Chen CM, Twu NF, Yen MS, Lai CR, Wu HH, Wang PH, Yuan CC (2009) Overexpression of Aurora B is associated with poor prognosis in epithelial ovarian cancer patients. Virchows Arch 455:431–440

  11. Chi P, Allis C, Wang GG (2010) Covalent histone modifications: miswritten, misinterpreted, and miserased in human cancers. Nat Rev Cancer 10:457–469

  12. Chodaparambil JV, Edayathumangalam RS, Bao Y, Park YJ, Luger K (2006) Nucleosome structure and function. Ernst Schering Res Found Workshop 57:29–46

  13. Costello JF, Frühwald MC, Smiraglia DJ, Rush LJ, Robertson GP, Gao X, Wright FA, Feramisco JD, Peltomäki P et al (2000) Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nat Genet 24:132–138

  14. Cress WD, Seto E (2000) Histone deacetylases, transcriptional control, and cancer. J Cell Physiol 184:1–16

  15. Crosio C, Cermakian N, Allis CD, Sassone-Corsi P (2000) Light induces chromatin modification in cells of the mammalian circadian clock. Nat Neurosci 3:1241–1247

  16. Curtis AM, Seo SB, Westgate EJ, Rudic RD, Smyth EM, Chakravarti D, FitzGerald GA, McNamara P (2004a) Histone acetyltransferase-dependent chromatin remodeling and the vascular clock. J Biol Chem 279:7091–7097

  17. Dai H, Zhang L, Cao M, Song F, Zheng H, Zhu X, Wei Q, Zhang W, Chen K (2011) The role of polymorphisms in circadian pathway genes in breast tumorigenesis. Breast Cancer Res 127:531–540

  18. Davie JR, Moniwa M (2000) Control of chromatin remodeling. Crit Rev Eukaryot Gene Expr 10:303–325

  19. Davis S, Mirick DK, Stevens RG (2001) Night shift work, light at night, and risk of breast cancer. J Natl Cancer Inst 93:1557–1562

  20. Doi M, Hirayama J, Sassone-Corsi P (2006) Circadian regulator CLOCK is a histone acetyltransferase. Cell 125:497–508

  21. Dong G, Yang Q, Wang Q, Kim YI, Wood TL, Osteryoung KW, van Oudenaarden A, Golden SS (2010) Elevated ATPase activity of KaiC applies a circadian checkpoint on cell division in Synechococcus elongatus. Cell 140:529–539

  22. Duong HA, Robles MS, Knutti D, Weitz CJ (2011) A molecular mechanism for circadian clock negative feedback. Science 332:1436–1439

  23. Eisele L, Prinz R, Klein-Hitpass L, Nückel H, Lowinski K, Thomale J, Moeller LC, Dührsen U, Dürig J (2009) Combined PER2 and CRY1 expression predicts outcome in chronic lymphocytic leukemia. Eur J Haematol 83:320–327

  24. Ekholm S, Reed S (2000) Regulation of G1 cyclin-dependent kinases in the mammalian cell cycle. Curr Opin Cell Biol 12:676–684

  25. Elshazley M, Sato M, Hase T, Yamashita R, Yoshida K, Toyokuni S, Ishiguro F, Osada H, Sekido Y, Yokoi K et al (2012) The circadian clock gene BMAL1 is a novel therapeutic target for malignant pleural mesothelioma. Int J Cancer 131:2820–2831

  26. Esteller M, Corn PG, Baylin SB, Herman JG (2001) A gene hypermethylation profile of human cancer. Cancer Res 61:3225–3229

  27. Etchegaray JP, Lee C, Wade PA, Reppert SM (2003) Rhythmic histone acetylation underlies transcription in the mammalian circadian clock. Nature 421:177–182

  28. Etchegaray JP, Yang X, DeBruyne JP, Peters AH, Weaver DR, Jenuwein T, Reppert SM (2006) The polycomb group protein EZH2 is required for mammalian circadian clock function. J Biol Chem 281:21209–21215

  29. Filipski E, Li XM, Lévi F (2006) Disruption of circadian coordination and malignant growth. Cancer Causes Control 7:509–514

  30. Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, Bonaldi T, Haydon C, Ropero S, Petrie K et al (2005) Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 37:391–400

  31. Fu L, Pelicano H, Liu J, Huang P, Lee CC (2002) The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell 111:41–50

  32. Garcia BA, Hake SB, Diaz RL, Kauer M, Morris SA, Recht J, Shabanowitz J, Mishra N, Strahl BD, Allis CD, Hunt DF (2007) Organismal differences in post-translational modifications in histones H3 and H4. J Biol Chem 282:7641–7655

  33. Gery S, Komatsu N, Baldjyan L, Yu A, Koo D, Koeffler HP (2006) The circadian gene per1 plays an important role in cell growth and DNA damage control in human cancer cells. Mol Cell 22:375–382

  34. Gery S, Komatsu N, Kawamata N, Miller CW, Desmond J, Virk RK, Marchevsky A, Mckenna R, Taguchi H, Koeffler HP (2007) Epigenetic silencing of the candidate tumor suppressor gene Per1 in non-small cell lung cancer. Clin Cancer Res 13:1399–1404

  35. Glaser KB, Staver MJ, Waring JF, Stender J, Ulrich RG, Davidsen SK (2003) Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines. Mol Cancer Ther 2:151–163

  36. Grant C, Rahman F, Piekarz R, Peer C, Frye R, Robey RW, Gardner ER, Figg WD, Bates SE (2010) Romidepsin: a new therapy for cutaneous T-cell lymphoma and a potential therapy for solid tumors. Expert Rev Anticancer Ther 10:997–1008

  37. Grechez-Cassiau SV, Reed SI (2000) Regulation of G1 cyclin-dependent kinases in the mammalian cell cycle. Curr Opin Cell Biol 12:676–684

  38. Grechez-Cassiau A, Rayet B, Guillaumond F, Teboul M, Delaunay F (2008) The circadian clock component BMAL1 is a critical regulator of p21WAF1/CIP1 expression and hepatocyte proliferation. J Biol Chem 283:4535–4542

  39. Greene MW (2012) Circadian rhythms and tumor growth. Cancer Lett 318:115–123

  40. Grimaldi B, Nakahata Y, Sahar S, Kaluzova M, Gauthier D, Pham K, Patel N, Hirayama J, Sassone-Corsi P (2007) Chromatin remodeling and circadian control: master regulator CLOCK is an enzyme. Cold Spring Harb Symp Quant Biol 72:105–112

  41. Haifa Abdulhaq MD, James M, Rossetti DO (2007) The role of azacitidine in the treatment of myelodysplastic syndromes. Expert Opin Investig Drugs 16:1967–1975

  42. Hansen J (2001) Light at night, shiftwork, and breast cancer risk. J Natl Cancer Inst 93:1513–1515

  43. Hernández-Rosas F, Hernández-Oliveras A, Flores-Peredo L, Rodríguez G, Zarain-Herzberg A, Caba M, Santiago-García J (2018) Histone-deacetylase inhibitors induce the expression of tumor suppressor genes Per1 and Per2 in human gastric cancer cells. Oncol Lett 16:1981–1990

  44. Hirayama J, Cardone L, Doi M, Sassone-Corsi P (2005) Common pathways in circadian and cell cycle clocks: light-dependentactivation of Fos/AP-1 in zebrafish controls CRY-1a and WEE-1. Proc Natl Acad Sci USA 102:10194–10199

  45. Hirayama J, Sahar S, Grimaldi B, Tamaru T, Takamatsu K, Nakahata Y, Sassone-Corsi P (2007) CLOCK-mediated acetylation of BMAL1 controls circadian function. Nature 450:1086–1090

  46. Hoffman AE, Yi CH, Zheng T, Stevens RG, Leaderer D, Zhang Y, Holford TR, Hansen J, Paulson J, Zhu Y (2010) CLOCK in breast tumorigenesis: genetic, epigenetic, and transcriptional profiling analyses. Cancer Res 70:1459–1468

  47. Jung-Hynes B, Schmit TL, Reagan-Shaw SR, Siddiqui IA, Mukhtar H, Ahmad N (2011) Melatonin, a novel Sirt1 inhibitor, imparts antiproliferative effects against prostate cancer in vitro in culture and in vivo in TRAMP model. J Pineal Res 50:140–149

  48. Katada S, Sassone-Corsi P (2010) The histone methyltransferase MLL1 permits the oscillation of circadian gene expression. Nat Struct Mol Biol 17:1414–1421

  49. Katada S, Imhof A, Sassone-Corsi P (2012) Connecting threads: epigenetics and metabolism. Cell 148:24–28

  50. Kettner NM, Katchy CA, Fu L (2014) Circadian gene variants in cancer. Ann Med 46:208–220

  51. 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 15:13

  52. Kim DH, Kim M, Kwo HJ (2003) Histone Deacetylase in carcinogenesis and its inhibitors as anti-cancer agents. Biochem Mol Biol J 36:110–119

  53. Klose RJ, Bird AP (2006) Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 31:89–97

  54. Kowalska E, Ripperger JA, Hoegger DC, Bruegger P, Buch T, Birchler T, Mueller A, Albrecht U, Contaldo C, Brown SA (2012) NONO couples the circadian clock to the cell cycle. Proc Natl Acad Sci USA 110:1592–1599

  55. Kulis M, Esteller M (2010) DNA methylation and cancer. In: Zdenko H, Toshikazu U (eds) Advances in genetics, vol 70. Academic Press, New York, pp 27–56

  56. 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 454:467–474

  57. Laranjeiro R, Tamai TK, Peyric E, Krusche P, Ott S, Whitmore D (2013) Cyclin-dependent kinase inhibitor p20 controls circadian cell-cycle timing. Proc Natl Acad Sci USA 110:6835–6840

  58. Lee CC (2006) Tumor suppression by the mammalian Period gene. Cancer Causes Control 17:525–553

  59. Lee S, Donehower LA, Herron AJ, Moore DD, Fu L (2010a) Disrupting circadian homeostasis of sympathetic signaling promotes tumor development in mice. PLoS ONE 5:e10995

  60. Lee Y, Lee J, Kwon I, Nakajima Y, Ohmiya Y, Son GH, Lee KH, Kim K (2010b) Coactivation of the CLOCK-BMAL1 complex by CBP mediates resetting of the circadian clock. J Cell Sci 123:3547–3557

  61. Lee HZ, Kwitkowski VE, Del Valle PL, Ricci MS, Saber H, Habtemariam BA, Bullock J, Bloomquist E, Li SY et al (2015) FDA approval: belinostat for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma. Clin Cancer Res 21:2666–2670

  62. Levi F, Okyar A, Dulong S, Innominato PF, Clairambault J, Levi F (2010) Circadian timing in cancer treatments. Annu Rev Pharmacol Toxicol 50:377–421

  63. Lewintre EJ, Martin CR, Ballesteros CG, Montaner D, Rivera RF, Mayans JR, García-Conde J (2009) Cryptochrome-1 expression: a new prognostic marker in B-cell chronic lymphocytic leukemia. Haematologica 94:280–284

  64. Lippman Z, May B, Yordan C, Singer T, Martienssen R (2003) Distinct mechanisms determine transposon inheritance and methylation via small interfering RNA and histone modification. PLoS Biol 1:e67

  65. Lowrey PL, Takahashi JS (2011) Genetics of circadian rhythms in mammalian model organisms. Adv Genet 74:175–230

  66. Luo W, Sehgal A (2005) Regulation of circadian behavioral output via a MicroRNAJAK/STAT circuit. Cell 148:765–779

  67. Luo J, Su F, Chen D, Shiloh A, Gu W (2000) Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature 408:377–381

  68. Masri S, Sassone-Corsi P (2010) Plasticity and specificity of the circadian epigenome. Nat Neurosci 13:1324–1329

  69. Masri S, Cervantes M, Sassone-Corsi P (2013) The circadian clock and cell cycle: interconnected biological circuits. Curr Opin Cell Biol 25:730–734

  70. Matsuo T, Yamaguchi S, Mitsui S, Emi A, Shimoda F, Okamura H (2003) Control mechanism of the circadian clock for timing of cell division in vivo. Science 302:255–259

  71. Monks A, Hose CD, Pezzoli P, Kondapaka S, Vansant G, Petersen KD, Sehested M, Monforte J, Shoemaker RH (2009) Gene expression-signature of belinostat in cell lines is specific for histone deacetylase inhibitor treatment, with a corresponding signature in xenografts. Anticancer Drugs 20:682–692

  72. Mori T, Binder B, Johnson CH (1996) Circadian gating of cell division in cyanobacteria growing with average doubling times of less than 24 hours. Proc Natl Acad Sci USA 93:10183–10188

  73. Mormont MC, Levi F (2003) Cancer chronotherapy: principles, applications, and perspectives. Cancer 98:881–882

  74. Mottet D, Castronovo V (2008) Histone de-acetylases: target enzymes for cancer therapy. Clin Exp Metastasis 25:183–189

  75. Mullenders J, Fabius AW, Madiredjo M, Bernards R, Beijersbergen RL (2009) A large scale shRNA barcode screen identifies the circadian clock component ARNTL as putative regulator of the p53 tumor suppressor pathway. PLoS ONE 4:e4798

  76. Nakahata Y, Kaluzova M, Grimaldi B, Sahar S, Hirayama J, Chen D, Guarente LP, Sassone-Corsi P (2008) The NAD+-dependent deacetylase SIRT1 modulates CLOCK mediated chromatin remodeling and circadian control. Cell 134:329–340

  77. Narasimamurthy R, Hatori M, Nayak SK, Liu F, Panda S, Verma IM (2012) Circadian clock protein cryptochrome regulates the expression of proinflammatory cytokines. Proc Natl Acad Sci USA 109:12662–12667

  78. Naruse Y, Oh-hashi K, Iijima N, Naruse M, Yoshioka H, Tanaka M (2004) Circadian and light-induced transcription of clock gene Per1 depends on histone acetylation and deacetylation. Mol Cell Biol 24:6278–6287

  79. Nebbioso A, Carafa V, Benedetti R, Altucci L (2012) Trials with “epigenetic” drugs: an update. Mol Oncol 6:657–682

  80. Oda A, Katayose Y, Yabuuchi S, Yamamoto K, Mizuma M, Shirasou S, Onogawa T, Ohtsuka H, Yoshida H et al (2009) Clock gene mouse period2 overexpression inhibits growth of human pancreatic cancer cells and has synergistic effect with cisplatin. Anticancer Res 29:1201–1209

  81. Panda S, Antoch MP, Miller BH, Su AI, Schook AB, Straume M, Schultz PG, Kay SA, Takahashi JS, Hogenesch JB (2002) Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109:307–320

  82. Pogue-Geile KL, Lyons-Weiler J, Whitcomb DC (2006) Molecular overlap of fly circadian rhythms and human pancreatic cancer. Cancer Lett 243:55–57

  83. Raedler LA (2016) Farydak (Panobinostat): first HDAC inhibitor approved for patients with relapsed multiple myeloma. Am Health Drug Benefits 9:84–87

  84. Rafnsson V, Tulinius H, Jonasson JG, Hrafnkelsson J (2001) Risk of breast cancer in female flight attendants: a population-based study (Iceland). Cancer Causes Control 12:95–101

  85. Ramsey KM, Yoshino J, Brace CS, Abrassart D, Kobayashi Y, Marcheva B, Hong HK, Chong JL, Buhr ED, Lee C et al (2009) Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science 324:651–654

  86. Relles D, Sendecki J, Chipitsyna G, Hyslop T, Yeo CJ, Arafat HA (2013) Circadian gene expression and clinicopathologic correlates in pancreatic cancer. J Gastrointest Surg 17:443–450

  87. Reppert SM, Weaver DR (2002) Coordination of circadian timing in mammals. Nature 418:935–941

  88. Ripperger JA, Schibler U (2006) Rhythmic CLOCK–BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions. Nat Genet 38:369–374

  89. Røe OD, Anderssen E, Helge E, Pettersen CH, Olsen KS, Sandeck H, Haaverstad R, Lundgren S, Larsson E (2009) Genome-wide profile of pleural mesothelioma versus parietal and visceral pleura: the emerging gene portrait of the mesothelioma phenotype. PLoS ONE 4:e6554

  90. Sawicka A, Seiser C (2014) Sensing core histone phosphorylation. A matter of perfect timing. Biochim Biophys Acta 1839:711–718

  91. Schernhammer ES, Laden F, Speizer FE, Willett WC, Hunter DJ, Kawachi I, Colditz GA (2001) Rotating night shifts and risk of breast cancer in women participating in the nurses’ health study. J Natl Cancer Inst 93:1563–1568

  92. Schernhammer ES, Holly JM, Hunter DJ, Pollak MN, Hankinson SE (2006) Insulin-like growth factor-I, its binding proteins (IGFBP-1 and IGFBP-3), and growth hormone and breast cancer risk in The Nurses Health Study II. Endocr Relat Cancer 13:583–592

  93. Sharrard RM, Royds JA, Rogers S, Shorthouse AJ (1992) Patterns of methylation of the c-myc gene in human colorectal cancer progression. Br J Cancer 65:667–672

  94. 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 45:732–740

  95. Siavoshian S, Segain JP, Kornprobst M, Bonnet C, Cherbut C, Galmiche JP, Blottière HM (2000) Butyrate and trichostatin A eVects on the proliferation/diVerentiation of human intestinal epithelial cells: induction of cyclin D3 and p21 expression. Gut 46:507–514

  96. Spanhoff A, Hauser AT, Heike R, Sippl W, Jung M (2009) The emerging therapeutic potential of histone methyltransferase and demethylase inhibitors. Chem Med Chem 4:1568–1582

  97. Sun CM, Huang SF, Zeng JM, Liu DB, Xiao Q, Tian WJ, Zhu XD, Huang Z, Feng WL (2010) Per2 inhibits k562 leukemia cell growth in vitro and in vivo through cell cycle arrest and apoptosis induction. Pathol Oncol Res 16:403–411

  98. Takahata S, Ozaki T, Mimura J, Kikuchi Y, Sogawa K, Fujii-Kuriyama Y (2000) Transactivation mechanisms of mouse clock transcription factors, mClock and mArnt3. Genes Cells 5:739–747

  99. Tamai TK, Young LC, Cox CA, Whitmore D (2012) Light acts on the zebrafish circadian clock to suppress rhythmic mitosis and cell proliferation. J Biol Rhythms 27:226–236

  100. Tanaka S, Arii S, Yasen M, Mogushi K, Su NT, Zhao C, Imoto I, Eishi Y, Inazawa J, Miki Y, Tanaka H (2008) Aurora kinase B is a predictive factor for the aggressive recurrence of hepatocellular carcinoma after curative hepatectomy. Br J Surg 95:611–619

  101. 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 69:8447–8454

  102. Tokunaga H, Takebayashi Y, Utsunomiya H, Akahira J, Higashimoto M, Mashiko M, Ito K, Niikura H, Takenoshita S, Yaegashi N (2008) Clinicopathological significance of circadian rhythm-related gene expression levels in patients with epithelial ovarian cancer. Acta Obstet Gynecol Scand 87:1060–1070

  103. Unsal-Kacmaz K, Mullen TE, Kaufmann WK, Sancar A (2005) Coupling of human circadian and cell cycles by the timeless protein. Mol Cell Biol 25:3109–3116

  104. Vachtenheim J, Horakova I, Novotna H (1994) Hypomethylation of CCGG sites in the 3' region of H-ras protooncogene is frequent and is associated with H-ras allele loss in non-small cell lung cancer. Cancer Res 54:1145–1148

  105. Van Dycke KC, Rodenburg W, Van Oostrom CT, VanKerkhof LW, Pennings JL, Roenneberg T, Van Steeg H, Vanderhorst GT (2015) Chronically alternating light cycles increase breast cancer risk in mice. Curr Biol 25:1932–1937

  106. Vincenzi B, Santini D, La Cesa A, Tonini G (2003) Cancer chronotherapy: principles, applications, and perspectives. Cancer 98:881–882

  107. Wang Y, Qian R, Sun N, Lu C, Chen Z, Hua L (2015) Circadian gene hClock enhances proliferation and inhibits apoptosis of human colorectal carcinoma cells in vitro and in vivo. Mol Med Rep 11:4204–4210

  108. Wood PA, Yang X, Taber A, Oh EY, Ansell C, Ayers SE, Al-Assaad Z, Carnevale K, Berger FG, Peña M, Hrushesky W (2008) Period 2 Mutation accelerates ApcMin/+ tumorigenesis. Mol Cancer Res 6:1786–1793

  109. Xia H, Niu Z, Ma H, Cao SZ, Hao SC, Liu ZT, Wang F (2010) Deregulated expression of the Per1 and Per2 in human gliomas. Can J Neurol Sci 37:365–370

  110. Xia L, Ma S, Zhang Y, Wang T, Zhou M (2015) Daily variation in global and local DNA methylation in mouse livers. PLoS ONE 10:e0118101

  111. Xiang S, Coffelt SB, Mao L, Yuan L, Cheng Q (2008) Period-2: a tumor suppressor gene in breast cancer. J Circadian Rhythms 6:4

  112. Xiao H, Hasegawa T, Isobe K (2000) p300 collaborates with Sp1 and Sp3 in p21 (waf1/cip1) promoter activation induced by histone deacetylase inhibitor. J Biol Chem 275:1371–1376

  113. Yang J, Kawai Y, Hanson RW, Arinze IJ (2001) Sodium butyrate induces transcription from the G alpha(i2) gene promoter through multiple Sp1 sites in the promoter and by activating the MEK-ERK signal transduction pathway. J Biol Chem 276:25742–25752

  114. Yang MY, Chang JG, Lin PM, Tang KP, Chen YH, Lin HY, Liu TC, Hsiao HH, Liu YC, Lin SF (2006) Downregulation of circadian clock genes in chronic myeloid leukemia: alternative methylation pattern of hPER3. Cancer Sci 97:1298–1307

  115. Yang X, Wood PA, Oh EY, Du-Quiton J, Ansell CM, Hrushesky WJ (2009) Down regulation of circadian clock gene Period 2 accelerates breast cancer growth by altering its daily growth rhythm. Breast Cancer Res Treat 117:423–431

  116. Yang MY, Yang WC, Lin PM, Hsu JF, Hsiao HH, Liu YC, Tsai HJ, Chang CS, Lin SF (2011) Altered expression of circadian clock genes in human chronic myeloid leukemia. J Biol Rhythms 26:136–148

  117. Ye Y, Xiang Y, Ozguc FM, Kim Y, Liu CJ, Park PK, Hu Q, Diao L, Lou Y, Lin C (2018) The genomic landscape and pharmacogenomic interactions of clock genes in cancer chronotherapy. Cell Syst 6:314–328.e2

  118. Yeh KT, Yang MY, Liu TC, Chen JC, Chan WL, Lin SF, Chang JG (2005) Abnormal expression of period 1 (PER1) in endometrial carcinoma. J Pathol 206:111–120

  119. Zhang Y, Reinberg D (2001) Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev 15:2343–2360

  120. Zhou F, He X, Liu H, Zhu Y, Jin T, Chen C, Qu F, Li Y, Bao G, Chen Z, Xing J (2012) Functional polymorphisms of circadian positive feedback regulation genes and clinical outcome of Chinese patients with resected colorectal cancer. Cancer 118:937–946

  121. Zhu Y, Leaderer D, Guss C, Brown HN, Zhang Y, Boyle P, Stevens RG, Hoffman A, Qin Q, Han X et al (2007) Ala394Thr polymorphism in the clock gene NPAS2: a circadian modifier for the risk of non-Hodgkin’s lymphoma. Int J Cancer 120:432–435

  122. Zhu Y, Stevens RG, Hoffman AE, Fitzgerald LM, Kwon EM, Ostrander EA, Davis S, Zheng T, Stanford JL (2009) Testing the circadian gene hypothesis in prostate cancer: a population-based case-control study. Cancer Res 69:9315–9322

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Correspondence to Fabiola Hernández-Rosas.

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Hernández-Rosas, F., López-Rosas, C.A. & Saavedra-Vélez, M.V. Disruption of the Molecular Circadian Clock and Cancer: An Epigenetic Link. Biochem Genet 58, 189–209 (2020). https://doi.org/10.1007/s10528-019-09938-w

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Keywords

  • Clock genes
  • Cancer
  • Circadian epigenome
  • Chromatin remodeling