Ras-Mediated Deregulation of the Circadian Clock in Cancer

English version České info

Living systems possess an endogenous time-generating system – the circadian clock - accountable for a 24 hours oscillation in the expression of about 10% of all genes. In mammals, disruption of oscillations is associated to several diseases including cancer. In this manuscript, we address the following question: what are the elicitors of a disrupted clock in cancer? We applied a systems biology approach to correlate experimental, bioinformatics and modelling data and could thereby identify key genes which discriminate strong and weak oscillators among cancer cell lines. Most of the discriminative genes play important roles in cell cycle regulation, DNA repair, immune system and metabolism and are involved in oncogenic pathways such as the RAS/MAPK. To investigate the potential impact of the Ras oncogene in the circadian clock we generated experimental models harbouring conditionally active Ras oncogenes. We put forward a direct correlation between the perturbation of Ras oncogene and an effect in the expression of clock genes, found by means of mathematical simulations and validated experimentally. Our study shows that perturbations of a single oncogene are sufficient to deregulate the mammalian circadian clock and opens new ways in which the circadian clock can influence disease and possibly play a role in therapy.

Vyšlo v časopise: Ras-Mediated Deregulation of the Circadian Clock in Cancer. PLoS Genet 10(5): e32767. doi:10.1371/journal.pgen.1004338
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004338

Souhrn

Zdroje

1. YoungMW, KaySA (2001) Time zones: a comparative genetics of circadian clocks. Nat Rev Genet 2: 702–715.

2. Bell-PedersenD, CassoneVM, EarnestDJ, GoldenSS, HardinPE, et al. (2005) Circadian rhythms from multiple oscillators: lessons from diverse organisms. Nat Rev Genet 6: 544–556.

3. PandaS, AntochMP, MillerBH, SuAI, SchookAB, et al. (2002) Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109: 307–320.

4. HankinsMW, PeirsonSN, FosterRG (2008) Melanopsin: an exciting photopigment. Trends Neurosci 31: 27–36.

5. StokkanKA, YamazakiS, TeiH, SakakiY, MenakerM (2001) Entrainment of the circadian clock in the liver by feeding. Science 291: 490–493.

6. SuterDM, SchiblerU (2009) Physiology. Feeding the clock. Science 326: 378–379.

7. AlbrechtU (2012) Timing to perfection: the biology of central and peripheral circadian clocks. Neuron 74: 246–260.

8. TakahashiJS, ShimomuraK, KumarV (2008) Searching for genes underlying behavior: lessons from circadian rhythms. Science 322: 909–912.

9. BrownSA, KowalskaE, DallmannR (2012) (Re)inventing the circadian feedback loop. Dev Cell 22: 477–487.

10. UedaHR, HayashiS, ChenW, SanoM, MachidaM, et al. (2005) System-level identification of transcriptional circuits underlying mammalian circadian clocks. Nat Genet 37: 187–192.

11. RelogioA, WestermarkPO, WallachT, SchellenbergK, KramerA, et al. (2011) Tuning the mammalian circadian clock: robust synergy of two loops. PLoS Comput Biol 7: e1002309.

12. WallachT, SchellenbergK, MaierB, KalathurRK, PorrasP, et al. (2013) Dynamic circadian protein-protein interaction networks predict temporal organization of cellular functions. PLoS Genet 9: e1003398.

13. BozekK, RelogioA, KielbasaSM, HeineM, DameC, et al. (2009) Regulation of clock-controlled genes in mammals. PLoS One 4: e4882.

14. BassJ (2012) Circadian topology of metabolism. Nature 491: 348–356.

15. MasriS, ZocchiL, KatadaS, MoraE, Sassone-CorsiP (2012) The circadian clock transcriptional complex: metabolic feedback intersects with epigenetic control. Ann N Y Acad Sci 1264: 103–109.

16. TakahashiJS, HongHK, KoCH, McDearmonEL (2008) The genetics of mammalian circadian order and disorder: implications for physiology and disease. Nat Rev Genet 9: 764–775.

17. SaharS, Sassone-CorsiP (2009) Metabolism and cancer: the circadian clock connection. Nat Rev Cancer 9: 886–896.

18. MatsuoT, YamaguchiS, MitsuiS, EmiA, ShimodaF, et al. (2003) Control mechanism of the circadian clock for timing of cell division in vivo. Science 302: 255–259.

19. KondratovaAA, KondratovRV (2012) The circadian clock and pathology of the ageing brain. Nat Rev Neurosci 13: 325–335.

20. FuL, LeeCC (2003) The circadian clock: pacemaker and tumour suppressor. Nat Rev Cancer 3: 350–361.

21. RafnssonV, TuliniusH, JonassonJG, HrafnkelssonJ (2001) Risk of breast cancer in female flight attendants: a population-based study (Iceland). Cancer Causes Control 12: 95–101.

22. KuboT, OzasaK, MikamiK, WakaiK, FujinoY, et al. (2006) Prospective cohort study of the risk of prostate cancer among rotating-shift workers: findings from the Japan collaborative cohort study. Am J Epidemiol 164: 549–555.

23. MormontMC, WaterhouseJ, BleuzenP, GiacchettiS, JamiA, et al. (2000) Marked 24-h rest/activity rhythms are associated with better quality of life, better response, and longer survival in patients with metastatic colorectal cancer and good performance status. Clin Cancer Res 6: 3038–3045.

24. FilipskiE, LeviF (2009) Circadian disruption in experimental cancer processes. Integr Cancer Ther 8: 298–302.

25. LeviF, OkyarA, DulongS, InnominatoPF, ClairambaultJ (2010) Circadian timing in cancer treatments. Annu Rev Pharmacol Toxicol 50: 377–421.

26. GeryS, KomatsuN, BaldjyanL, YuA, KooD, et al. (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.

27. HoffmanAE, ZhengT, StevensRG, BaY, ZhangY, et al. (2009) Clock-cancer connection in non-Hodgkin's lymphoma: a genetic association study and pathway analysis of the circadian gene cryptochrome 2. Cancer Res 69: 3605–3613.

28. FuL, PelicanoH, LiuJ, HuangP, LeeC (2002) The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell 111: 41–50.

29. LisCG, GrutschJF, WoodP, YouM, RichI, et al. (2003) Circadian timing in cancer treatment: the biological foundation for an integrative approach. Integr Cancer Ther 2: 105–111.

30. LeviF, SchiblerU (2007) Circadian rhythms: mechanisms and therapeutic implications. Annu Rev Pharmacol Toxicol 47: 593–628.

31. BernardS, Cajavec BernardB, LeviF, HerzelH (2010) Tumor growth rate determines the timing of optimal chronomodulated treatment schedules. PLoS Comput Biol 6: e1000712.

32. HrusheskyWJ, GrutschJ, WoodP, YangX, OhEY, et al. (2009) Circadian clock manipulation for cancer prevention and control and the relief of cancer symptoms. Integr Cancer Ther 8: 387–397.

33. InnominatoPF, LeviFA, BjarnasonGA (2010) Chronotherapy and the molecular clock: Clinical implications in oncology. Adv Drug Deliv Rev 62: 979–1001.

34. GaddameedhiS, ReardonJT, YeR, OzturkN, SancarA (2012) Effect of circadian clock mutations on DNA damage response in mammalian cells. Cell Cycle 11: 3481–3491.

35. SancarA, Lindsey-BoltzLA, KangTH, ReardonJT, LeeJH, et al. (2010) Circadian clock control of the cellular response to DNA damage. FEBS Lett 584: 2618–2625.

36. KowalskaE, RippergerJA, HoeggerDC, BrueggerP, BuchT, et al. (2012) NONO couples the circadian clock to the cell cycle. Proc Natl Acad Sci U S A 110: 1592–9.

37. BorgsL, BeukelaersP, VandenboschR, BelachewS, NguyenL, et al. (2009) Cell “circadian” cycle: new role for mammalian core clock genes. Cell Cycle 8: 832–837.

38. WoodPA, Du-QuitonJ, YouS, HrusheskyWJ (2006) Circadian clock coordinates cancer cell cycle progression, thymidylate synthase, and 5-fluorouracil therapeutic index. Mol Cancer Ther 5: 2023–2033.

39. NakahataY, SaharS, AstaritaG, KaluzovaM, Sassone-CorsiP (2009) Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1. Science 324: 654–657.

40. BrooksCL, GuW (2009) How does SIRT1 affect metabolism, senescence and cancer? Nat Rev Cancer 9: 123–128.

41. KondratovRV, AntochMP (2007) Circadian proteins in the regulation of cell cycle and genotoxic stress responses. Trends Cell Biol 17: 311–317.

42. ChenST, ChooKB, HouMF, YehKT, KuoSJ, et al. (2005) Deregulated expression of the PER1, PER2 and PER3 genes in breast cancers. Carcinogenesis 26: 1241–1246.

43. HuaH, WangY, WanC, LiuY, ZhuB, et al. (2006) Circadian gene mPer2 overexpression induces cancer cell apoptosis. Cancer Sci 97: 589–596.

44. Chen-GoodspeedM, LeeCC (2007) Tumor suppression and circadian function. J Biol Rhythms 22: 291–298.

45. YangWS, StockwellBR (2008) Inhibition of casein kinase 1-epsilon induces cancer-cell-selective, PERIOD2-dependent growth arrest. Genome Biol 9: R92.

46. YiCH, ZhengT, LeadererD, HoffmanA, ZhuY (2009) Cancer-related transcriptional targets of the circadian gene NPAS2 identified by genome-wide ChIP-on-chip analysis. Cancer Lett 284: 149–156.

47. AlhopuroP, BjorklundM, SammalkorpiH, TurunenM, TuupanenS, et al. (2010) Mutations in the circadian gene CLOCK in colorectal cancer. Mol Cancer Res 8: 952–960.

48. LeviF, FilipskiE, IurisciI, LiXM, InnominatoP (2007) Cross-talks between circadian timing system and cell division cycle determine cancer biology and therapeutics. Cold Spring Harb Symp Quant Biol 72: 465–475.

49. ZhangEE, LiuAC, HirotaT, MiragliaLJ, WelchG, et al. (2009) A genome-wide RNAi screen for modifiers of the circadian clock in human cells. Cell 139: 199–210.

50. ThomasP, StarlingerJ, VowinkelA, ArztS, LeserU (2012) GeneView: a comprehensive semantic search engine for PubMed. Nucleic Acids Res 40: W585–591.

51. WaltherA, JohnstoneE, SwantonC, MidgleyR, TomlinsonI, et al. (2009) Genetic prognostic and predictive markers in colorectal cancer. Nat Rev Cancer 9: 489–499.

52. SzklarczykD, FranceschiniA, KuhnM, SimonovicM, RothA, et al. (2010) The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Res 39: D561–568.

53. SchroderK, HertzogPJ, RavasiT, HumeDA (2004) Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol 75: 163–189.

54. FusenigNE, BoukampP (1998) Multiple stages and genetic alterations in immortalization, malignant transformation, and tumor progression of human skin keratinocytes. Mol Carcinog 23: 144–158.

55. LiuHS, ScrableH, VillaretDB, LiebermanMA, StambrookPJ (1992) Control of Ha-ras-mediated mammalian cell transformation by Escherichia coli regulatory elements. Cancer Res 52: 983–989.

56. ShirasawaS, FuruseM, YokoyamaN, SasazukiT (1993) Altered growth of human colon cancer cell lines disrupted at activated Ki-ras. Science 260: 85–88.

57. ShiSQ, AnsariTS, McGuinnessOP, WassermanDH, JohnsonCH (2013) Circadian disruption leads to insulin resistance and obesity. Curr Biol 23: 372–381.

58. KondratovRV, KondratovaAA, GorbachevaVY, VykhovanetsOV, AntochMP (2006) Early aging and age-related pathologies in mice deficient in BMAL1, the core componentof the circadian clock. Genes Dev 20: 1868–1873.

59. JanichP, PascualG, Merlos-SuarezA, BatlleE, RippergerJ, et al. (2011) The circadian molecular clock creates epidermal stem cell heterogeneity. Nature 480: 209–214.

60. BallestaA, DulongS, AbbaraC, CohenB, OkyarA, et al. (2011) A combined experimental and mathematical approach for molecular-based optimization of irinotecan circadian delivery. PLoS Comput Biol 7: e1002143.

61. LiQ, WangX, LuZ, ZhangB, GuanZ, et al. (2010) Polycomb CBX7 directly controls trimethylation of histone H3 at lysine 9 at the p16 locus. PLoS One 5: e13732.

62. KimMS, ChungNG, KangMR, YooNJ, LeeSH (2011) Genetic and expressional alterations of CHD genes in gastric and colorectal cancers. Histopathology 58: 660–668.

63. WuS, ShiY, MulliganP, GayF, LandryJ, et al. (2007) A YY1-INO80 complex regulates genomic stability through homologous recombination-based repair. Nat Struct Mol Biol 14: 1165–1172.

64. MajumderP, GomezJA, ChadwickBP, BossJM (2008) The insulator factor CTCF controls MHC class II gene expression and is required for the formation of long-distance chromatin interactions. J Exp Med 205: 785–798.

65. MajumderP, BossJM (2010) CTCF controls expression and chromatin architecture of the human major histocompatibility complex class II locus. Mol Cell Biol 30: 4211–4223.

66. MerkenschlagerM, OdomDT (2013) CTCF and Cohesin: Linking Gene Regulatory Elements with Their Targets. Cell 152: 1285–1297.

67. Sassone-CorsiP (2013) Physiology. When metabolism and epigenetics converge. Science 339: 148–150.

68. Sassone-CorsiP (2012) Minireview: NAD+, a circadian metabolite with an epigenetic twist. Endocrinology 153: 1–5.

69. FengD, LazarMA (2012) Clocks, metabolism, and the epigenome. Mol Cell 47: 158–167.

70. ParkJI, KwakJY (2012) The role of peroxisome proliferator-activated receptors in colorectal cancer. PPAR Res 2012: 876418.

71. BradshawAD (2012) Diverse biological functions of the SPARC family of proteins. Int J Biochem Cell Biol 44: 480–488.

72. MohamedMM, SloaneBF (2006) Cysteine cathepsins: multifunctional enzymes in cancer. Nat Rev Cancer 6: 764–775.

73. CanoA, SantamariaPG, Moreno-BuenoG (2012) LOXL2 in epithelial cell plasticity and tumor progression. Future Oncol 8: 1095–1108.

74. Sossey-AlaouiK, LiX, RanalliTA, CowellJK (2005) WAVE3-mediated cell migration and lamellipodia formation are regulated downstream of phosphatidylinositol 3-kinase. J Biol Chem 280: 21748–21755.

75. YeDZ, KaestnerKH (2009) Foxa1 and Foxa2 control the differentiation of goblet and enteroendocrine L- and D-cells in mice. Gastroenterology 137: 2052–2062.

76. HossainMN, SakemuraR, FujiiM, AyusawaD (2006) G-protein gamma subunit GNG11 strongly regulates cellular senescence. Biochem Biophys Res Commun 351: 645–650.

77. MatiseLA, PalmerTD, AshbyWJ, NashabiA, ChytilA, et al. (2012) Lack of transforming growth factor-beta signaling promotes collective cancer cell invasion through tumor-stromal crosstalk. Breast Cancer Res 14: R98.

78. HarmanFS, NicolCJ, MarinHE, WardJM, GonzalezFJ, et al. (2004) Peroxisome proliferator-activated receptor-delta attenuates colon carcinogenesis. Nat Med 10: 481–483.

79. LuoF, BrooksDG, YeH, HamoudiR, PoulogiannisG, et al. (2009) Mutated K-ras(Asp12) promotes tumourigenesis in Apc(Min) mice more in the large than the small intestines, with synergistic effects between K-ras and Wnt pathways. Int J Exp Pathol 90: 558–574.

80. SpenglerML, KuropatwinskiKK, SchumerM, AntochMP (2009) A serine cluster mediates BMAL1-dependent CLOCK phosphorylation and degradation. Cell Cycle 8: 4138–4146.

81. OshimaT, TakenoshitaS, AkaikeM, KunisakiC, FujiiS, et al. (2011) Expression of circadian genes correlates with liver metastasis and outcomes in colorectal cancer. Oncol Rep 25: 1439–1446.

82. LengyelZ, LovigC, KommedalS, KeszthelyiR, SzekeresG, et al. (2012) Altered expression patterns of clock gene mRNAs and clock proteins in human skin tumors. Tumour Biol 34: 811–819.

83. OshimaT, TakenoshitaS, AkaikeM, KunisakiC, FujiiS, et al. Expression of circadian genes correlates with liver metastasis and outcomes in colorectal cancer. Oncol Rep 25: 1439–1446.

84. SanadaK, OkanoT, FukadaY (2002) Mitogen-activated protein kinase phosphorylates and negatively regulates basic helix-loop-helix-PAS transcription factor BMAL1. J Biol Chem 277: 267–271.

85. WilliamsJA, SuHS, BernardsA, FieldJ, SehgalA (2001) A circadian output in Drosophila mediated by neurofibromatosis-1 and Ras/MAPK. Science 293: 2251–2256.

86. WeberF, HungHC, MaurerC, KaySA (2006) Second messenger and Ras/MAPK signalling pathways regulate CLOCK/CYCLE-dependent transcription. J Neurochem 98: 248–257.

87. NomuraK, TakeuchiY, FukunagaK (2006) MAP kinase additively activates the mouse Per1 gene promoter with CaM kinase II. Brain Res 1118: 25–33.

88. HakenbergJ, GernerM, HaeusslerM, SoltI, PlakeC, et al. (2011) The GNAT library for local and remote gene mention normalization. Bioinformatics 27: 2769–2771.

89. AirolaA, PyysaloS, BjorneJ, PahikkalaT, GinterF, et al. (2008) All-paths graph kernel for protein-protein interaction extraction with evaluation of cross-corpus learning. BMC Bioinformatics 9 Suppl 11: S2.

90. TikkD, ThomasP, PalagaP, HakenbergJ, LeserU (2010) A comprehensive benchmark of kernel methods to extract protein-protein interactions from literature. PLoS Comput Biol 6: e1000837.

91. SayersEW, BarrettT, BensonDA, BoltonE, BryantSH, et al. (2011) Database resources of the National Center for Biotechnology Information. Nucleic Acids Res 40: D13–25.

92. KauffmannA, GentlemanR, HuberW (2009) arrayQualityMetrics–a bioconductor package for quality assessment of microarray data. Bioinformatics 25: 415–416.

93. IrizarryRA, BolstadBM, CollinF, CopeLM, HobbsB, et al. (2003) Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res 31: e15.

94. SmythGK (2004) Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3: Article3.

95. JeanmouginM, de ReyniesA, MarisaL, PaccardC, NuelG, et al. (2010) Should we abandon the t-test in the analysis of gene expression microarray data: a comparison of variance modeling strategies. PLoS One 5: e12336.

96. KooperbergC, AragakiA, StrandAD, OlsonJM (2005) Significance testing for small microarray experiments. Stat Med 24: 2281–2298.

97. MurieC, WoodyO, LeeAY, NadonR (2009) Comparison of small n statistical tests of differential expression applied to microarrays. BMC Bioinformatics 10: 45.

98. JefferyIB, HigginsDG, CulhaneAC (2006) Comparison and evaluation of methods for generating differentially expressed gene lists from microarray data. BMC Bioinformatics 7: 359.

99. McCallMN, JaffeeHA, IrizarryRA (2012) fRMA ST: frozen robust multiarray analysis for Affymetrix Exon and Gene ST arrays. Bioinformatics 28: 3153–3154.

100. SporlF, SchellenbergK, BlattT, WenckH, WitternKP, et al. (2010) A circadian clock in HaCaT keratinocytes. J Invest Dermatol 131: 338–348.

101. YooSH, YamazakiS, LowreyPL, ShimomuraK, KoCH, et al. (2004) PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc Natl Acad Sci U S A 101: 5339–5346.

102. SatoT, VriesRG, SnippertHJ, van de WeteringM, BarkerN, et al. (2009) Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459: 262–265.

103. BrownSA, Fleury-OlelaF, NagoshiE, HauserC, JugeC, et al. (2005) The period length of fibroblast circadian gene expression varies widely among human individuals. PLoS Biol 3: e338.