The emerging link between cancer, metabolism, and circadian rhythms

Abstract

The circadian clock is a complex cellular mechanism that, through the control of diverse metabolic and gene expression pathways, governs a large array of cyclic physiological processes. Epidemiological and clinical data reveal a connection between the disruption of circadian rhythms and cancer that is supported by recent preclinical data. In addition, results from animal models and molecular studies underscore emerging links between cancer metabolism and the circadian clock. This has implications for therapeutic approaches, and we discuss the possible design of chronopharmacological strategies.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: The mammalian circadian clock.
Fig. 2: The molecular components of the mammalian circadian clock.
Fig. 3: Circadian regulation of tumor initiation and progression.
Fig. 4: Tumor–host communication involving circadian metabolic tissues.

References

  1. 1.

    Fu, L. & Lee, C. C. The circadian clock: pacemaker and tumour suppressor. Nat. Rev. Cancer 3, 350–361 (2003).

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Sahar, S. & Sassone-Corsi, P. Metabolism and cancer: the circadian clock connection. Nat. Rev. Cancer 9, 886–896 (2009).

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Masri, S., Kinouchi, K. & Sassone-Corsi, P. Circadian clocks, epigenetics, and cancer. Curr. Opin. Oncol. 27, 50–56 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Lie, J. A., Roessink, J. & Kjaerheim, K. Breast cancer and night work among Norwegian nurses. Cancer Causes Control 17, 39–44 (2006).

    Article  PubMed  Google Scholar 

  5. 5.

    Papantoniou, K. et al. Night shift work, chronotype and prostate cancer risk in the MCC-Spain case-control study. Int. J. Cancer 137, 1147–1157 (2015).

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Schernhammer, E. S. et al. Rotating night shifts and risk of breast cancer in women participating in the nurses’ health study. J. Natl. Cancer. Inst. 93, 1563–1568 (2001).

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Straif, K. et al. Carcinogenicity of shift-work, painting, and fire-fighting. Lancet. Oncol. 8, 1065–1066 (2007).

    Article  PubMed  Google Scholar 

  8. 8.

    Knutsson, A. et al. Breast cancer among shift workers: results of the WOLF longitudinal cohort study. Scand. J. Work. Environ. Health 39, 170–177 (2013).

    Article  PubMed  Google Scholar 

  9. 9.

    Kakizaki, M. et al. Sleep duration and the risk of prostate cancer: the Ohsaki Cohort Study. Br. J. Cancer 99, 176–178 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Srour, B. et al. Circadian nutritional behaviours and cancer risk: new insights from the NutriNet-sante prospective cohort study: disclaimers. Int. J. Cancer 143, 2369–2379 (2018).

  11. 11.

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

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Lee, S., Donehower, L. A., Herron, A. J., Moore, D. D. & Fu, L. Disrupting circadian homeostasis of sympathetic signaling promotes tumor development in mice. PLoS One 5, e10995 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Papagiannakopoulos, T. et al. Circadian rhythm disruption promotes lung tumorigenesis. Cell. Metab. 24, 324–331 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Filipski, E. et al. Host circadian clock as a control point in tumor progression. J. Natl. Cancer. Inst. 94, 690–697 (2002).

    Article  PubMed  Google Scholar 

  15. 15.

    Chen, S. T. et al. Deregulated expression of the PER1, PER2 and PER3 genes in breast cancers. Carcinogenesis 26, 1241–1246 (2005).

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Taniguchi, H. et al. Epigenetic inactivation of the circadian clock gene BMAL1 in hematologic malignancies. Cancer Res. 69, 8447–8454 (2009).

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Zhu, Y. et al. Epigenetic impact of long-term shiftwork: pilot evidence from circadian genes and whole-genome methylation analysis. Chronobiol. Int. 28, 852–861 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Filipski, E. et al. Effects of chronic jet lag on tumor progression in mice. Cancer Res. 64, 7879–7885 (2004).

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Kettner, N. M. et al. Circadian homeostasis of liver metabolism suppresses hepatocarcinogenesis. Cancer Cell. 30, 909–924 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Asher, G. & Sassone-Corsi, P. Time for food: the intimate interplay between nutrition, metabolism, and the circadian clock. Cell 161, 84–92 (2015).

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Marcheva, B. et al. Circadian clocks and metabolism. Handb. Exp. Pharmacol. 217, 127–155 (2013).

    CAS  Article  Google Scholar 

  22. 22.

    Abbondante, S., Eckel-Mahan, K. L., Ceglia, N. J., Baldi, P. & Sassone-Corsi, P. Comparative circadian metabolomics reveal differential effects of nutritional challenge in the serum and liver. J. Biol. Chem. 291, 2812–2828 (2016).

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Eckel-Mahan, K. L. et al. Reprogramming of the circadian clock by nutritional challenge. Cell 155, 1464–1478 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Hatori, M. et al. Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Cell. Metab. 15, 848–860 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Altman, B. J. et al. MYC disrupts the circadian clock and metabolism in cancer cells. Cell. Metab. 22, 1009–1019 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  Article  Google Scholar 

  27. 27.

    Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    CAS  Article  Google Scholar 

  28. 28.

    Gaucher, J., Montellier, E. & Sassone-Corsi, P. Molecular cogs: interplay between circadian clock and cell cycle. Trends. Cell Biol. 28, 368–379 (2018).

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Jackson, E. L. et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 15, 3243–3248 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

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

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Walhout, A. J., Gubbels, J. M., Bernards, R., van der Vliet, P. C. & Timmers, H. T. c-Myc/Max heterodimers bind cooperatively to the E-box sequences located in the first intron of the rat ornithine decarboxylase (ODC) gene. Nucleic Acids Res. 25, 1493–1501 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Huber, A. L. et al. CRY2 and FBXL3 cooperatively degrade c-MYC. Mol. Cell 64, 774–789 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Shostak, A. et al. MYC/MIZ1-dependent gene repression inversely coordinates the circadian clock with cell cycle and proliferation. Nat. Commun. 7, 11807 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Chaix, A., Zarrinpar, A., Miu, P. & Panda, S. Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges. Cell. Metab. 20, 991–1005 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Tognini, P. et al. Distinct circadian signatures in liver and gut clocks revealed by ketogenic diet. Cell. Metab. 26, 523–538 e525 (2017).

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Oishi, K., Uchida, D. & Itoh, N. Low-carbohydrate, high-protein diet affects rhythmic expression of gluconeogenic regulatory and circadian clock genes in mouse peripheral tissues. Chronobiol. Int. 29, 799–809 (2012).

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Dyar, K. A. et al. Atlas of circadian metabolism reveals system-wide coordination and communication between clocks. Cell 174, 1571–1585. e11 (2018).

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Kohsaka, A. et al. High-fat diet disrupts behavioral and molecular circadian rhythms in mice. Cell. Metab. 6, 414–421 (2007).

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Vollmers, C. et al. Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression. Proc. Natl. Acad. Sci. USA 106, 21453–21458 (2009).

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Damiola, F. et al. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev. 14, 2950–2961 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Stokkan, K. A., Yamazaki, S., Tei, H., Sakaki, Y. & Menaker, M. Entrainment of the circadian clock in the liver by feeding. Science 291, 490–493 (2001).

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Dallmann, R., Viola, A. U., Tarokh, L., Cajochen, C. & Brown, S. A. The human circadian metabolome. Proc. Natl. Acad. Sci. USA 109, 2625–2629 (2012).

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Sato, S., Parr, E. B., Devlin, B. L., Hawley, J. A. & Sassone-Corsi, P. Human metabolomics reveal daily variations under nutritional challenges specific to serum and skeletal muscle. Mol. Metab. 16, 1–11 (2018).

  44. 44.

    Wu, Y. et al. Reciprocal regulation between the circadian clock and hypoxia signaling at the genome level in mammals. Cell. Metab. 25, 73–85 (2017).

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Adamovich, Y., Ladeuix, B., Golik, M., Koeners, M. P. & Asher, G. Rhythmic oxygen levels reset circadian clocks through HIF1α. Cell. Metab. 25, 93–101 (2017).

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Peek, C. B. et al. Circadian clock interaction with HIF1α mediates oxygenic metabolism and anaerobic glycolysis in skeletal muscle. Cell. Metab. 25, 86–92 (2017).

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Arendt, J., Bojkowski, C., Franey, C., Wright, J. & Marks, V. Immunoassay of 6-hydroxymelatonin sulfate in human plasma and urine: abolition of the urinary 24-h rhythm with atenolol. J. Clin. Endocrinol. Metab. 60, 1166–1173 (1985).

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Zawilska, J. B., Skene, D. J. & Arendt, J. Physiology and pharmacology of melatonin in relation to biological rhythms. Pharmacol. Rep. 61, 383–410 (2009).

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Reiter, R. J., Tan, D. X., Manchester, L. C. & Qi, W. Biochemical reactivity of melatonin with reactive oxygen and nitrogen species: a review of the evidence. Cell Biochem. Biophys. 34, 237–256 (2001).

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Reiter, R. J., Tan, D. X., Manchester, L. C. & El-Sawi, M. R. Melatonin reduces oxidant damage and promotes mitochondrial respiration: implications for aging. Ann. NY Acad. Sci. 959, 238–250 (2002).

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Leon, J., Acuna-Castroviejo, D., Escames, G., Tan, D. X. & Reiter, R. J. Melatonin mitigates mitochondrial malfunction. J. Pineal Res. 38, 1–9 (2005).

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Martin, M. et al. Melatonin-induced increased activity of the respiratory chain complexes I and IV can prevent mitochondrial damage induced by ruthenium red in vivo. J. Pineal Res. 28, 242–248 (2000).

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Proietti, S., Cucina, A., Minini, M. & Bizzarri, M. Melatonin, mitochondria, and the cancer cell. Cell. Mol. Life Sci. 74, 4015–4025 (2017).

  54. 54.

    Bhatti, P., et al. Oxidative DNA damage during night shift work. Occup. Environ. Med. 74, 680–683. (2017).

  55. 55.

    Al-Zoughbi, W. et al. Tumor macroenvironment and metabolism. Semin. Oncol. 41, 281–295 (2014).

    Article  CAS  PubMed  Google Scholar 

  56. 56.

    Lee, Y. M., Chang, W. C. & Ma, W. L. Hypothesis: solid tumours behave as systemic metabolic dictators. J. Cell. Mol. Med. 20, 1076–1085 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Rutkowski, M. R., Svoronos, N., Perales-Puchalt, A. & Conejo-Garcia, J. R. The tumor macroenvironment: cancer-promoting networks beyond tumor beds. Adv. Cancer Res. 128, 235–262 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Masri, S. et al. Lung adenocarcinoma distally rewires hepatic circadian homeostasis. Cell 165, 896–909 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Hojo, H. et al. Remote reprogramming of hepatic circadian transcriptome by breast cancer. Oncotarget 8, 34128–34140 (2017).

    PubMed  PubMed Central  Google Scholar 

  60. 60.

    Brady, J. J. et al. Lung adenocarcinoma distally rewires hepatic circadian homeostasis. Cancer Cell. 29, 697–710 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Hensley, C. T. et al. Metabolic heterogeneity in human lung tumors. Cell 164, 681–694 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Faubert, B. et al. Lactate metabolism in human lung tumors. Cell 171, 358–371 e359 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Hui, S. et al. Glucose feeds the TCA cycle via circulating lactate. Nature 551, 115–118 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Spinelli, J. B., et al. Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass. Science 358, 941–946 (2017).

  65. 65.

    Bass, J. & Takahashi, J. S. Circadian integration of metabolism and energetics. Science 330, 1349–1354 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Dallmann, R., Okyar, A. & Levi, F. Dosing-time makes the poison: circadian regulation and pharmacotherapy. Trends Mol. Med. 22, 430–445 (2016).

    CAS  Article  PubMed  Google Scholar 

  67. 67.

    Svensson, R. U. et al. Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nat. Med. 22, 1108–1119 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Comerford, S. A. et al. Acetate dependence of tumors. Cell 159, 1591–1602 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Schug, Z. T. et al. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell. 27, 57–71 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Sahar, S. Circadian control of fatty acid elongation by SIRT1-mediated deacetylation of Acetyl-CoA synthetase 1. J. Biol. Chem. 289, 6091–6097 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Sulli, G. et al. Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence. Nature 553, 351–355 (2018).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Gui, D. Y. et al. Environment dictates dependence on mitochondrial complex i for nad+ and aspartate production and determines cancer cell sensitivity to metformin. Cell. Metab. 24, 716–727 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Asher, G. et al. SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 134, 317–328 (2008).

    CAS  Article  PubMed  Google Scholar 

  74. 74.

    Nakahata, Y. et al. The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134, 329–340 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Masri, S. et al. Partitioning circadian transcription by SIRT6 leads to segregated control of cellular metabolism. Cell 158, 659–672 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Aguilar-Arnal, L., Katada, S., Orozco-Solis, R. & Sassone-Corsi, P. NAD + –SIRT1 control of H3K4 trimethylation through circadian deacetylation of MLL1. Nat. Struct. Mol. Biol. 22, 312–318 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Nakahata, Y., Sahar, S., Astarita, G., Kaluzova, M. & Sassone-Corsi, P. Circadian control of the NAD+salvage pathway by CLOCK-SIRT1. Science 324, 654–657 (2009).

    CAS  Article  PubMed  Google Scholar 

  78. 78.

    Ramsey, K. M. et al. Circadian clock feedback cycle through NAMPT-mediated NAD+biosynthesis. Science 324, 651–654 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Fang, M., Guo, W. R., Park, Y., Kang, H. G. & Zarbl, H. Enhancement of NAD+-dependent SIRT1 deacetylase activity by methylselenocysteine resets the circadian clock in carcinogen-treated mammary epithelial cells. Oncotarget 6, 42879–42891 (2015).

    PubMed  PubMed Central  Google Scholar 

  80. 80.

    Nahimana, A. et al. The NAD biosynthesis inhibitor APO866 has potent antitumor activity against hematologic malignancies. Blood 113, 3276–3286 (2009).

    CAS  Article  PubMed  Google Scholar 

  81. 81.

    Thakur, B. K. et al. Involvement of p53 in the cytotoxic activity of the NAMPT inhibitor FK866 in myeloid leukemic cells. Int. J. Cancer 132, 766–774 (2013).

    CAS  Article  PubMed  Google Scholar 

  82. 82.

    Puram, R. V. et al. Core circadian clock genes regulate leukemia stem cells in AML. Cell 165, 303–316 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Barberino, R. S. et al. Melatonin protects against cisplatin-induced ovarian damage in mice via the MT1 receptor and antioxidant activity. Biol. Reprod. 96, 1244–1255 (2017).

    Article  PubMed  Google Scholar 

  84. 84.

    Gao, Y. Melatonin synergizes the chemotherapeutic effect of 5-fluorouracil in colon cancer by suppressing PI3K/AKT and NF-κB/iNOS signaling pathways. J. Pineal Res. 62, e12380 (2017).

    Article  CAS  Google Scholar 

  85. 85.

    Goncalves Ndo, N. et al. Effect of melatonin in epithelial mesenchymal transition markers and invasive properties of breast cancer stem cells of canine and human cell lines. PLoS One 11, e0150407 (2016).

    Article  CAS  PubMed  Google Scholar 

  86. 86.

    Mao, L. et al. Circadian gating of epithelial-to-mesenchymal transition in breast cancer cells via melatonin-regulation of GSK3β. Mol. Endocrinol. 26, 1808–1820 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Lissoni, P., Chilelli, M., Villa, S., Cerizza, L. & Tancini, G. Five years survival in metastatic non-small cell lung cancer patients treated with chemotherapy alone or chemotherapy and melatonin: a randomized trial. J. Pineal Res. 35, 12–15 (2003).

    CAS  Article  PubMed  Google Scholar 

  88. 88.

    Del Fabbro, E., Dev, R., Hui, D., Palmer, L. & Bruera, E. Effects of melatonin on appetite and other symptoms in patients with advanced cancer and cachexia: a double-blind placebo-controlled trial. J. Clin. Oncol. 31, 1271–1276 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Mayers, J. R. et al. Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat. Med. 20, 1193–1198 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Nishiumi, S. et al. A novel serum metabolomics-based diagnostic approach for colorectal cancer. PLoS One 7, e40459 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Jobard, E. et al. A serum nuclear magnetic resonance-based metabolomic signature of advanced metastatic human breast cancer. Cancer Lett. 343, 33–41 (2014).

    CAS  Article  PubMed  Google Scholar 

  92. 92.

    Kobayashi, T. et al. A novel serum metabolomics-based diagnostic approach to pancreatic cancer. Cancer Epidemiol. Biomarkers. Prev. 22, 571–579 (2013).

    CAS  Article  PubMed  Google Scholar 

  93. 93.

    Wei, S. et al. Metabolomics approach for predicting response to neoadjuvant chemotherapy for breast cancer. Mol. Oncol. 7, 297–307 (2013).

    CAS  Article  PubMed  Google Scholar 

  94. 94.

    Aviram, R. et al. Lipidomics analyses reveal temporal and spatial lipid organization and uncover daily oscillations in intracellular organelles. Mol. Cell 62, 636–648 (2016).

    CAS  Article  PubMed  Google Scholar 

  95. 95.

    Eckel-Mahan, K. L. et al. Coordination of the transcriptome and metabolome by the circadian clock. Proc. Natl. Acad. Sci. USA 109, 5541–5546 (2012).

    CAS  Article  PubMed  Google Scholar 

  96. 96.

    Haus, E., Lakatua, D. J., Swoyer, J. & Sackett-Lundeen, L. Chronobiology in hematology and immunology. Am. J. Anat. 168, 467–517 (1983).

    CAS  Article  PubMed  Google Scholar 

  97. 97.

    Scheiermann, C., Kunisaki, Y. & Frenette, P. S. Circadian control of the immune system. Nat. Rev. Immunol. 13, 190–198 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Partch, C. L., Green, C. B. & Takahashi, J. S. Molecular architecture of the mammalian circadian clock. Trends. Cell Biol. 24, 90–99 (2014).

    CAS  Article  PubMed  Google Scholar 

  99. 99.

    Bass, J. Circadian topology of metabolism. Nature 491, 348–356 (2012).

    CAS  Article  PubMed  Google Scholar 

  100. 100.

    Gekakis, N. et al. Role of the CLOCK protein in the mammalian circadian mechanism. Science 280, 1564–1569 (1998).

    CAS  Article  PubMed  Google Scholar 

  101. 101.

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Panda, S. et al. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109, 307–320 (2002).

    CAS  Article  PubMed  Google Scholar 

  103. 103.

    Akhtar, R. A. et al. Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus. Curr. Biol. 12, 540–550 (2002).

    CAS  Article  PubMed  Google Scholar 

  104. 104.

    Koike, N. et al. Transcriptional architecture and chromatin landscape of the core circadian clock in mammals. Science 338, 349–354 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Rey, G. et al. Genome-wide and phase-specific DNA-binding rhythms of BMAL1 control circadian output functions in mouse liver. PLoS Biol. 9, e1000595 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Duong, H. A., Robles, M. S., Knutti, D. & Weitz, C. J. A molecular mechanism for circadian clock negative feedback. Science 332, 1436–1439 (2011).

    CAS  Article  PubMed  Google Scholar 

  107. 107.

    Preitner, N. et al. The orphan nuclear receptor REV-ERBα controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110, 251–260 (2002).

    CAS  Article  PubMed  Google Scholar 

  108. 108.

    Sato, T. K. et al. A functional genomics strategy reveals Rora as a component of the mammalian circadian clock. Neuron 43, 527–537 (2004).

    CAS  Article  PubMed  Google Scholar 

  109. 109.

    Masri, S. & Sassone-Corsi, P. The circadian clock: a framework linking metabolism, epigenetics and neuronal function. Nat. Rev. Neurosci. 14, 69–75 (2013).

    CAS  Article  PubMed  Google Scholar 

  110. 110.

    Welsh, D. K., Takahashi, J. S. & Kay, S. A. Suprachiasmatic nucleus: cell autonomy and network properties. Annu. Rev. Physiol. 72, 551–577 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Yamazaki, S. et al. Resetting central and peripheral circadian oscillators in transgenic rats. Science 288, 682–685 (2000).

    CAS  Article  PubMed  Google Scholar 

  112. 112.

    Welsh, D. K., Logothetis, D. E., Meister, M. & Reppert, S. M. Individual neurons dissociated from rat suprachiasmatic nucleus express independently phased circadian firing rhythms. Neuron 14, 697–706 (1995).

    CAS  Article  PubMed  Google Scholar 

  113. 113.

    Reppert, S. M. & Weaver, D. R. Molecular analysis of mammalian circadian rhythms. Annu. Rev. Physiol. 63, 647–676 (2001).

    CAS  Article  PubMed  Google Scholar 

  114. 114.

    Welsh, D. K., Yoo, S. H., Liu, A. C., Takahashi, J. S. & Kay, S. A. Bioluminescence imaging of individual fibroblasts reveals persistent, independently phased circadian rhythms of clock gene expression. Curr. Biol. 14, 2289–2295 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Pando, M. P., Morse, D., Cermakian, N. & Sassone-Corsi, P. Phenotypic rescue of a peripheral clock genetic defect via SCN hierarchical dominance. Cell 110, 107–117 (2002).

    CAS  Article  PubMed  Google Scholar 

  116. 116.

    Thresher, R. J. et al. Role of mouse cryptochrome blue-light photoreceptor in circadian photoresponses. Science 282, 1490–1494 (1998).

    CAS  Article  PubMed  Google Scholar 

  117. 117.

    Hirayama, J. et al. CLOCK-mediated acetylation of BMAL1 controls circadian function. Nature 450, 1086–1090 (2007).

    CAS  Article  PubMed  Google Scholar 

  118. 118.

    Nader, N., Chrousos, G. P. & Kino, T. Circadian rhythm transcription factor CLOCK regulates the transcriptional activity of the glucocorticoid receptor by acetylating its hinge region lysine cluster: potential physiological implications. FASEB J. 23, 1572–1583 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  119. 119.

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

    CAS  Article  PubMed  Google Scholar 

  120. 120.

    Hung, H. C., Maurer, C., Kay, S. A. & Weber, F. Circadian transcription depends on limiting amounts of the transcription co-activator nejire/CBP. J. Biol. Chem. 282, 31349–31357 (2007).

    CAS  Article  PubMed  Google Scholar 

  121. 121.

    Hosoda, H. et al. CBP/p300 is a cell type-specific modulator of CLOCK/BMAL1-mediated transcription. Mol. Brain 2, 34 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Feng, D. et al. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science 331, 1315–1319 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Alenghat, T. et al. Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology. Nature 456, 997–1000 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Chang, H. C. & Guarente, L. SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Cell 153, 1448–1460 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  125. 125.

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

    CAS  Article  PubMed  Google Scholar 

  126. 126.

    Valekunja, U. K. et al. Histone methyltransferase MLL3 contributes to genome-scale circadian transcription. Proc. Natl. Acad. Sci. USA 110, 1554–1559 (2013).

    CAS  Article  PubMed  Google Scholar 

  127. 127.

    Janich, P. et al. The circadian molecular clock creates epidermal stem cell heterogeneity. Nature 480, 209–214 (2011).

    CAS  Article  PubMed  Google Scholar 

  128. 128.

    Sato, S. et al. Circadian reprogramming in the liver identifies metabolic pathways of aging. Cell 170, 664–677.e11 (2017).

    CAS  Article  PubMed  Google Scholar 

  129. 129.

    Solanas, G. et al. Aged stem cells reprogram their daily rhythmic functions to adapt to stress. Cell 170, 678–692.e20 (2017).

    CAS  Article  PubMed  Google Scholar 

  130. 130.

    Plikus, M. V. et al. Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration. Nature 451, 340–344 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Mendez-Ferrer, S., Lucas, D., Battista, M. & Frenette, P. S. Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452, 442–447 (2008).

    CAS  Article  PubMed  Google Scholar 

  132. 132.

    Geyfman, M. et al. Brain and muscle Arnt-like protein-1 (BMAL1) controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis. Proc. Natl. Acad. Sci. USA 109, 11758–11763 (2012).

    CAS  Article  PubMed  Google Scholar 

  133. 133.

    Hoffman, A. E. et al. CLOCK in breast tumorigenesis: genetic, epigenetic, and transcriptional profiling analyses. Cancer Res. 70, 1459–1468 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Hoffman, A. E. et al. The core circadian gene Cryptochrome 2 influences breast cancer risk, possibly by mediating hormone signaling. Cancer Prev. Res. (Phila) 3, 539–548 (2010).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

The Masri laboratory is supported by a K22 Transition Career Development Award through the National Cancer Institute (NCI), the Concern Foundation, and the V Foundation for Cancer Research. Work in the Sassone-Corsi laboratory is supported by NIH (National Institutes of Health), INSERM (Institut National de la Sante et la Recherche Medicale, France), and KAUST (King Abdullah University of Science and Technology, Saudi Arabia).

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Selma Masri or Paolo Sassone-Corsi.

Ethics declarations

Competing interests

The authors declare no conflicts of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Masri, S., Sassone-Corsi, P. The emerging link between cancer, metabolism, and circadian rhythms. Nat Med 24, 1795–1803 (2018). https://doi.org/10.1038/s41591-018-0271-8

Download citation

Further reading