Potential Role of Circadian Clock in Cancer Evolution: History
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Contributor:
Yool Lee
,
Alfian Shan Tanggono

Circadian rhythms, including sleep/wake cycles as well as hormonal, immune, metabolic, and cell proliferation rhythms, are fundamental biological processes driven by a cellular time-keeping system called the circadian clock. Disruptions in these rhythms due to genetic alterations or irregular lifestyles cause fundamental changes in physiology, from metabolism to cellular proliferation and differentiation, resulting in pathological consequences including cancer. Cancer cells are not uniform and static but exist as different subtypes with phenotypic and functional differences in the tumor microenvironment. At the top of the heterogeneous tumor cell hierarchy, cancer stem cells (CSCs), a self-renewing and multi-potent cancer cell type, are most responsible for tumor recurrence and metastasis, chemoresistance, and mortality. Phenotypically, CSCs are associated with the epithelial-mesenchymal transition (EMT), which confers cancer cells with increased motility and invasion ability that is characteristic of malignant and drug-resistant stem cells. Recently, emerging studies of different cancer types, such as glioblastoma, leukemia, prostate cancer, and breast cancer, suggest that the circadian clock plays an important role in the maintenance of CSC/EMT characteristics.

  • circadian clock
  • cancer stem cells
  • epithelial–mesenchymal transition

1. Introduction

Circadian clocks are cell-autonomous timing systems that generate roughly 24 h periodic rhythms and are conserved in nearly all life, from unicellular organisms to humans. These internal timing systems integrate with diverse environmental (e.g., light, temperature) and metabolic (e.g., food intake) stimuli to regulate a myriad of temporal biological activities, including sleep/wake, feeding times, energy metabolism, hormonal and immune functions, and cellular proliferation and differentiation [1]. Evolutionarily, these flexible clock systems are thought to help organisms survive better by increasing their ability to timely anticipate and adapt to the cyclic changes of light and food availability as well as predation risk [2][3]. At the unicellular level, as in the case of all prokaryotes that are classified into bacteria and archaea, the timely compartmentalization of biochemical and redox processes by the intrinsic circadian clock ensures the temporal fitness of cell physiology and functions across species [4]. In lower eukaryotic species, including yeast and fungi, biological timekeepers may help these single-celled organisms escape the DNA-damaging effects of ionizing radiation from sunlight as well as oxidative stress during cell division [5][6][7]. In higher, complex organisms, such as most vertebrate species, including humans, multi-stimuli responsive oscillators in neurons and fibroblasts are tightly coupled to form the brain and peripheral organ clock systems, which, in turn, constitute a body-wide circadian network with adaptive capacity for the environmental entrainment of rhythmic behaviors and physiology [8].
In contrast to the evolutionarily adaptive benefits of circadian rhythms, rhythm disruptions, primarily due to modern lifestyles lacking regular patterns of working, eating, and sleeping, have been recognized to increase the susceptibility of humans to the onset and development of cardio-metabolic and immune disorders as well as multiple types of cancers [9][10][11][12]. Furthermore, several studies of animal models possessing genetic mutations in clock genes or exposed to forced circadian desynchrony regimens have strengthened the causal relationship between circadian disturbances and pathological consequences [13][14][15][16]. In particular, genetic and environmental perturbations of circadian rhythms largely alter the expressions and activities of several tumor suppressors and oncogenes in both host and tumor tissues in favor of cancer incidence and progression [17][18]. These circadian disruptions also reprogram host metabolism and immune systems, facilitating an immunosuppressive tumor microenvironment and enabling tumor progression and metastasis of multiple cancer types [13][14][19].
One of the most formidable issues in cancer diagnosis and treatment is cancer cell heterogeneity and plasticity, the adaptive capacity of diverse cancer cell populations to survive upon tumor-environmental challenges [20]. Cancer cells in tumor tissues are not uniform, but consist of distinct types of cell subpopulations that can change their cellular morphology, physiology, and behavior in response to tumor-intrinsic and extrinsic changes (e.g., gene mutations, low nutrient or oxygen levels, immune surveillance, or toxic drug exposure) [20][21]. Among the different tumor cell populations, the cancer stem cell (CSC), a self-renewing cancer cell type with multi-differentiation potential, is highly responsible for tumor recurrence and metastasis, therapy resistance, and mortality [21]. The generation of tumor cells with stem cell properties has been closely linked to the epithelial–mesenchymal transition (EMT), a process that increases the migratory and invasive capacities of cancer cells, leading to drug-resistance and metastatic potential in CSC populations [22][23]. Accordingly, effective eradication of these deadly cell populations during chemotherapeutic intervention is becoming more important for improved therapeutic outcomes. Growing evidence suggests that the cellular heterogeneity observed in several cancer types is not just genetically determined but also arises from inherent cancer cell plasticity instructed by the tumor-extrinsic microenvironment [24][25][26][27][28].

2. The Molecular Clockwork and Circadian System

In all living organisms, the basic biological timing unit is the cell. In mammals, including humans, circadian rhythms are primarily driven by a cell-autonomous molecular feedback mechanism in which the circadian transcriptional activators aryl hydrocarbon receptor nuclear translocator-like (BMAL1) and circadian locomotor output cycles kaput (CLOCK) cyclically activate the expressions of their own repressors, period (PER) and cryptochrome (CRY) [29]. The core oscillator is complemented by a second loop in which cycling expression of BMAL1 is maintained by the REV-ERBα/β repressor and RORα/β activator proteins [29] (Figure 1A). Besides the core regulatory loops, multiple levels of epigenetic, posttranscriptional, and posttranslational regulation involving various kinases, phosphatases, ubiquitin-proteasome pathway components, nuclear-cytoplasmic transporters, non-coding RNAs, and chromatin remodelers contribute to the molecular clockwork, thus coordinating temporal programs via multiple clock-output genes involved in cellular physiology and metabolism [30][31][32][33][34][35][36][37]. The core clock machinery is mobilized to reset cellular rhythms upon intrinsic and extrinsic stimuli involving multiple post-translational (e.g., phosphorylation, sumoylation) and metabolic (e.g., Ca2+, cAMP) signaling pathways [32][36][38][39]. Systemically, oscillators that respond to multiple stimuli in neurons and fibroblasts are tightly coupled to form the brain and peripheral organ clock systems, which, in turn, constitute a body-wide circadian network with adaptive synchronous capacity for environmental entrainment of rhythmic behaviors (e.g., sleep/wake and feed/fast cycles) and physiology (e.g., temperature, blood pressure, energy metabolism, immune functions, cellular proliferation and differentiation) [30]. In particular, the hypothalamic suprachiasmatic nucleus (SCN), a central circadian pacemaker in the brain, communicates retinal light input to peripheral clock systems, thus mediating periodic synchronization of internal body rhythms with external day and night cycles [40] (Figure 1B). Besides SCN-mediated photic entrainment, a growing number of studies report that non-SCN brain regions (e.g., substantia nigra [SN], nucleus accumbens [NA], arcuate nucleus [ARC], choroid plexus [CR]), and peripheral tissues (e.g., liver, kidney, muscle, and adipose) possess their own autonomous and muti-stimuli entrainable oscillators that influence not only circadian functions in the SCN and neighboring local clocks, but also whole body rhythms via neural, hormonal, and metabolic feedback mechanisms [11][41][42][43][44][45][46][47][48][49].
Figure 1. The core circadian timing systems in mammals. (A) Schematic of the molecular mechanisms of the circadian clock oscillator. At the molecular level, the circadian loop consists of a core loop and a stabilizing loop. In the core loop, the heterodimer BMAL1/CLOCK binds to the E box enhancer element (E) of the PER and CRY genes to initiate transcription. PER and CRY proteins accumulate before they heterodimerize and act as a transcriptional repressor. Expression of BMAL1, a core clock gene, is controlled by an ROR/REV-ERB-response element (RORE)-dependent mechanism, which plays an important role in stabilizing the period of the molecular circadian clock. (B) The suprachiasmatic nucleus (SCN), a small region in the brain, represents the highest hierarchy of core clock functions. When light stimuli are transmitted to the SCN through the retinohypothalamic tract (RHT), the SCN acts as a central pacemaker to synchronize the circadian clocks present in peripheral organs and coordinate temporal physiology. However, non-photic external cues (e.g., temperature changes, food intake, metabolic stimuli, hormonal changes) can reset circadian rhythms in peripheral clock tissues, thereby influencing the rhythmic output of physiology and behaviors.

3. Circadian Disruption and Cancer Pathogenesis

Mirroring the interactive features of biological clock systems, studies in both human and animal models have suggested that daily mismatches between the internal body clock and environmental cycles, such as irregular work (e.g., night shift) and life schedules (e.g., jet lag, mistimed eating), cause physiological complications that increase the risk of cardiac, metabolic, neurological, and neoplastic diseases [9][10][11][12]. Globally, artificial light sources in modern society are a primary contributor to disrupted circadian rhythmicity. Eighty percent of the world’s population is now exposed to light during the night, and about 18–20% of workers in the USA and Europe are engaged in night or rotating shift work, which predisposes them to multiple rhythm disorders, particularly cancer [50]. Indeed, several epidemiological studies suggest that night shift work and chronic jet lag increase the risks of onset and development of the most common cancer types (i.e., breast, lung, prostate, colorectal, and skin cancers) [51]. Based on such accumulating evidence, the International Agency for Research on Cancer (IARC) classified “shift-work that involves circadian disruption” as potentially “carcinogenic to humans (Group 2A)” in 2007 [52] and again in 2019 [53]. Besides work-related disruptions, additional factors that alter circadian rhythms, such as abnormal lighting conditions [54], irregular eating habits [55], and traumatic stress [56], may also contribute to tumor pathogenesis and progression. For example, a recent population-based case–control study reported that mistimed eating patterns increased the risks of breast and prostate cancers [57]. Overall, these findings underscore the importance of maintaining normal circadian rhythms for the prevention and management of cancer.

4. The Circadian Clock and Cancer Cell Proliferation

The relevance of the circadian clock to cancer pathophysiology has mainly been attributed to the regulatory relationship between the circadian clock and cell proliferation. Accumulating studies have unraveled molecular connections between the circadian clock and cell cycle-regulating factors [58][59]. Indeed, most of the genes regulating critical steps in the phases of the cell cycle have been found to be controlled by the circadian clock. For instance, c-MYC and cyclin D1, which induce entry into the DNA synthesis (S) phase, as well as WEE1, which controls entry into the mitosis (M) phase, exhibit circadian cycles of expression in a CLOCK/BMAL1-dependent manner [17][58][60][61][62]. There are also other cell cycle regulators and checkpoint controllers (e.g., p21, p16/INK4a, p27, and p57), as well as cell cycle signaling pathway factors (e.g., mitogen-activated protein kinase (MAPK), Wnt/β-catenin, and transforming growth factor (TGF)), that are regulated by the circadian clock to mediate daily cycles of cell proliferation [63]. Furthermore, the DNA damage response, DNA repair mechanisms, and apoptotic signaling pathways, which are closely associated with cell cycle checkpoints, are directly controlled by circadian clock components, such as CLOCK, PER1/2, and CRY1/2 in the core loop and RORA and NR1D1/2 in the stabilizing loop, of the molecular clockwork [64][65][66][67][68][69][70].
Notably, a growing number of studies have suggested direct roles of clock genes in tumor proliferation and growth. For example, genetic or epigenetic silencing of BMAL1 and/or CLOCK has been shown to increase tumor proliferation or growth rates in hematologic cancer [71], colon cancer [72], pancreatic cancer [73], tongue squamous cell carcinoma (TSCC) [74], breast cancer [75], lung adenocarcinoma [18], hepatocellular carcinoma (HCC) [76], nasopharyngeal carcinoma (NPC) [77], and glioblastoma multiforme (GBM) [78]. Conversely, overexpression of these clock activators suppresses the proliferative and malignant properties of tumor cells via cell cycle arrest and p53-dependent apoptosis [78][79]. In line with this, downregulation or upregulation of the BMAL1/CLOCK target genes PER1, PER2, and CRY1 promote or suppress tumor onset and proliferation, respectively, in Lewis lung carcinoma (LLC), mammary carcinoma [80], pancreatic cancer [81], lung carcinoma [18], leukemia [82][83], glioma [84], ovarian cancer [85], and oral squamous cell carcinoma [86][87]. At the molecular level, these studies suggest that the anti-cancer activity exerted by PER1/2 occurs via the inhibition of PI3K/AKT/mTOR-mediated glycolysis as well as cell cycle arrest and apoptosis induction [80][86][87]. In addition, recent studies from the Lamia group have reported that CRY1 and/or CRY2 promote the degradation of cMYC, early 2 factor (E2F) family members, and tousled like kinase 2 (TLK2) by recruiting these cell cycle-related oncogenic factors to the SCFFBXL3 ubiquitin-ligase complex [88]. Correlating with this, a recent large-scale systems analysis of 32 human cancer types has revealed that PERs and CRYs, along with several other clock genes, are downregulated in several types of cancers [89]. Taken together, these findings indicate that core clock components have tumor suppressor functions in most cancer types. However, most of these chrono-cancer studies have been based on bulk analyses of tumor cells grown in monolayer cultures or on tumor tissues grafted in mice, which are unable to recapitulate the spatiotemporal variations in phenotypes or the functions of distinct cancer cell populations in tumors under normal or abnormal circadian conditions [17].

This entry is adapted from the peer-reviewed paper 10.3390/ijms232214181

References

  1. Patke, A.; Young, M.W.; Axelrod, S. Molecular mechanisms and physiological importance of circadian rhythms. Nat. Rev. Mol. Cell Biol. 2019, 21, 67–84.
  2. Bass, J.; Lazar, M.A. Circadian time signatures of fitness and disease. Science 2016, 354, 994–999.
  3. Dunlap, J.C. Molecular bases for circadian clocks. Cell 1999, 96, 271–290.
  4. Edgar, R.S.; Green, E.W.; Zhao, Y.; van Ooijen, G.; Olmedo, M.; Qin, X.; Xu, Y.; Pan, M.; Valekunja, U.K.; Feeney, K.A.; et al. Peroxiredoxins are conserved markers of circadian rhythms. Nature 2012, 485, 459–464.
  5. Causton, H.C.; Feeney, K.A.; Ziegler, C.A.; O’Neill, J.S. Metabolic Cycles in Yeast Share Features Conserved among Circadian Rhythms. Curr. Biol. 2015, 25, 1056–1062.
  6. Chaix, A.; Zarrinpar, A.; Panda, S. The circadian coordination of cell biology. J. Cell Biol. 2016, 215, 15–25.
  7. Baker, C.L.; Loros, J.J.; Dunlap, J.C. The circadian clock of Neurospora crassa. FEMS Microbiol. Rev. 2012, 36, 95–110.
  8. Lee, Y.; Wisor, J.P. Multi-Modal Regulation of Circadian Physiology by Interactive Features of Biological Clocks. Biology 2021, 11, 21.
  9. Logan, R.W.; McClung, C.A. Rhythms of life: Circadian disruption and brain disorders across the lifespan. Nat. Rev. Neurosci. 2019, 20, 49–65.
  10. Scheiermann, C.; Gibbs, J.; Ince, L.; Loudon, A. Clocking in to immunity. Nat. Rev. Immunol. 2018, 18, 423–437.
  11. Segers, A.; Depoortere, I. Circadian clocks in the digestive system. Nat. Rev. Gastroenterol. Hepatol. 2021, 18, 239–251.
  12. Masri, S.; Sassone-Corsi, P. The emerging link between cancer, metabolism, and circadian rhythms. Nat. Med. 2018, 24, 1795–1803.
  13. Aiello, I.; Fedele, M.L.M.; Roman, F.; Marpegan, L.; Caldart, C.; Chiesa, J.J.; Golombek, D.A.; Finkielstein, C.V.; Paladino, N. Circadian disruption promotes tumor-immune microenvironment remodeling favoring tumor cell proliferation. Sci. Adv. 2020, 6, eaaz4530.
  14. Hadadi, E.; Taylor, W.; Li, X.M.; Aslan, Y.; Villote, M.; Riviere, J.; Duvallet, G.; Auriau, C.; Dulong, S.; Raymond-Letron, I.; et al. Chronic circadian disruption modulates breast cancer stemness and immune microenvironment to drive metastasis in mice. Nat. Commun. 2020, 11, 3193.
  15. Mattis, J.; Sehgal, A. Circadian Rhythms, Sleep, and Disorders of Aging. Trends Endocrinol. Metab. 2016, 27, 192–203.
  16. Shafi, A.A.; McNair, C.M.; McCann, J.J.; Alshalalfa, M.; Shostak, A.; Severson, T.M.; Zhu, Y.; Bergman, A.; Gordon, N.; Mandigo, A.C.; et al. The circadian cryptochrome, CRY1, is a pro-tumorigenic factor that rhythmically modulates DNA repair. Nat. Commun. 2021, 12, 401.
  17. Lee, Y.; Lahens, N.F.; Zhang, S.; Bedont, J.; Field, J.M.; Sehgal, A. G1/S cell cycle regulators mediate effects of circadian dysregulation on tumor growth and provide targets for timed anticancer treatment. PLoS Biol. 2019, 17, e3000228.
  18. Papagiannakopoulos, T.; Bauer, M.R.; Davidson, S.M.; Heimann, M.; Subbaraj, L.; Bhutkar, A.; Bartlebaugh, J.; Vander Heiden, M.G.; Jacks, T. Circadian Rhythm Disruption Promotes Lung Tumorigenesis. Cell Metab. 2016, 24, 324–331.
  19. Hadadi, E.; Acloque, H. Role of circadian rhythm disorders on EMT and tumour-immune interactions in endocrine-related cancers. Endocr.-Relat. Cancer 2021, 28, R67–R80.
  20. Yuan, S.; Norgard, R.J.; Stanger, B.Z. Cellular Plasticity in Cancer. Cancer Discov. 2019, 9, 837–851.
  21. Das, P.K.; Pillai, S.; Rakib, M.A.; Khanam, J.A.; Gopalan, V.; Lam, A.K.Y.; Islam, F. Plasticity of Cancer Stem Cell: Origin and Role in Disease Progression and Therapy Resistance. Stem Cell Rev. Rep. 2020, 16, 397–412.
  22. Shibue, T.; Weinberg, R.A. EMT, CSCs, and drug resistance: The mechanistic link and clinical implications. Nat. Rev. Clin. Oncol. 2017, 14, 611–629.
  23. Dongre, A.; Weinberg, R.A. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat. Rev. Mol. Cell Biol. 2019, 20, 69–84.
  24. Anderson, A.R.; Weaver, A.M.; Cummings, P.T.; Quaranta, V. Tumor morphology and phenotypic evolution driven by selective pressure from the microenvironment. Cell 2006, 127, 905–915.
  25. Arozarena, I.; Wellbrock, C. Phenotype plasticity as enabler of melanoma progression and therapy resistance. Nat. Rev. Cancer 2019, 19, 377–391.
  26. Dirkse, A.; Golebiewska, A.; Buder, T.; Nazarov, P.V.; Muller, A.; Poovathingal, S.; Brons, N.H.C.; Leite, S.; Sauvageot, N.; Sarkisjan, D.; et al. Stem cell-associated heterogeneity in Glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment. Nat. Commun. 2019, 10, 1787.
  27. Zhou, Y.; Yang, D.; Yang, Q.; Lv, X.; Huang, W.; Zhou, Z.; Wang, Y.; Zhang, Z.; Yuan, T.; Ding, X.; et al. Single-cell RNA landscape of intratumoral heterogeneity and immunosuppressive microenvironment in advanced osteosarcoma. Nat. Commun. 2020, 11, 6322.
  28. Sharma, A.; Merritt, E.; Hu, X.; Cruz, A.; Jiang, C.; Sarkodie, H.; Zhou, Z.; Malhotra, J.; Riedlinger, G.M.; De, S. Non-Genetic Intra-Tumor Heterogeneity Is a Major Predictor of Phenotypic Heterogeneity and Ongoing Evolutionary Dynamics in Lung Tumors. Cell Rep. 2019, 29, 2164–2174.e5.
  29. Takahashi, J.S. Transcriptional architecture of the mammalian circadian clock. Nat. Rev. Genet. 2017, 18, 164–179.
  30. Koronowski, K.B.; Sassone-Corsi, P. Communicating clocks shape circadian homeostasis. Science 2021, 371, eabd0951.
  31. Anafi, R.C.; Lee, Y.; Sato, T.K.; Venkataraman, A.; Ramanathan, C.; Kavakli, I.H.; Hughes, M.E.; Baggs, J.E.; Growe, J.; Liu, A.C.; et al. Machine learning helps identify CHRONO as a circadian clock component. PLoS Biol. 2014, 12, e1001840.
  32. Lee, Y.; Lee, J.; Kwon, I.; Nakajima, Y.; Ohmiya, Y.; Son, G.H.; Lee, K.H.; Kim, K. Coactivation of the CLOCK-BMAL1 complex by CBP mediates resetting of the circadian clock. J. Cell Sci. 2010, 123 Pt 20, 3547–3557.
  33. Lee, J.; Lee, Y.; Lee, M.J.; Park, E.; Kang, S.H.; Chung, C.H.; Lee, K.H.; Kim, K. Dual modification of BMAL1 by SUMO2/3 and ubiquitin promotes circadian activation of the CLOCK/BMAL1 complex. Mol. Cell. Biol. 2008, 28, 6056–6065.
  34. Lee, Y.; Shen, Y.; Francey, L.J.; Ramanathan, C.; Sehgal, A.; Liu, A.C.; Hogenesch, J.B. The NRON complex controls circadian clock function through regulated PER and CRY nuclear translocation. Sci. Rep. 2019, 9, 11883.
  35. Lee, Y.; Jang, A.R.; Francey, L.J.; Sehgal, A.; Hogenesch, J.B. KPNB1 mediates PER/CRY nuclear translocation and circadian clock function. eLife 2015, 4, e08647.
  36. Lee, Y.; Chun, S.K.; Kim, K. Sumoylation controls CLOCK-BMAL1-mediated clock resetting via CBP recruitment in nuclear transcriptional foci. Biochim. Biophys. Acta 2015, 1853 Pt A, 2697–2708.
  37. Korge, S.; Maier, B.; Bruning, F.; Ehrhardt, L.; Korte, T.; Mann, M.; Herrmann, A.; Robles, M.S.; Kramer, A. The non-classical nuclear import carrier Transportin 1 modulates circadian rhythms through its effect on PER1 nuclear localization. PLoS Genet. 2018, 14, e1007189.
  38. Shim, H.S.; Kim, H.; Lee, J.; Son, G.H.; Cho, S.; Oh, T.H.; Kang, S.H.; Seen, D.S.; Lee, K.H.; Kim, K. Rapid activation of CLOCK by Ca2+-dependent protein kinase C mediates resetting of the mammalian circadian clock. EMBO Rep. 2007, 8, 366–371.
  39. Travnickova-Bendova, Z.; Cermakian, N.; Reppert, S.M.; Sassone-Corsi, P. Bimodal regulation of mPeriod promoters by CREB-dependent signaling and CLOCK/BMAL1 activity. Proc. Natl. Acad. Sci. USA 2002, 99, 7728–7733.
  40. Kudo, T.; Block, G.D.; Colwell, C.S. The Circadian Clock Gene Period1 Connects the Molecular Clock to Neural Activity in the Suprachiasmatic Nucleus. ASN Neuro 2015, 7, 6.
  41. Hasegawa, S.; Fukushima, H.; Hosoda, H.; Serita, T.; Ishikawa, R.; Rokukawa, T.; Kawahara-Miki, R.; Zhang, Y.; Ohta, M.; Okada, S.; et al. Hippocampal clock regulates memory retrieval via Dopamine and PKA-induced GluA1 phosphorylation. Nat. Commun. 2019, 10, 5766.
  42. Myung, J.; Schmal, C.; Hong, S.; Tsukizawa, Y.; Rose, P.; Zhang, Y.; Holtzman, M.J.; De Schutter, E.; Herzel, H.; Bordyugov, G.; et al. The choroid plexus is an important circadian clock component. Nat. Commun. 2018, 9, 1062.
  43. Son, G.H.; Chung, S.; Choe, H.K.; Kim, H.D.; Baik, S.M.; Lee, H.; Lee, H.W.; Choi, S.; Sun, W.; Kim, H.; et al. Adrenal peripheral clock controls the autonomous circadian rhythm of glucocorticoid by causing rhythmic steroid production. Proc. Natl. Acad. Sci. USA 2008, 105, 20970–20975.
  44. Ehlen, J.C.; Brager, A.J.; Baggs, J.; Pinckney, L.; Gray, C.L.; DeBruyne, J.P.; Esser, K.A.; Takahashi, J.S.; Paul, K.N. Bmal1 function in skeletal muscle regulates sleep. eLife 2017, 6, e26557.
  45. Myung, J.; Wu, M.Y.; Lee, C.Y.; Rahim, A.R.; Truong, V.H.; Wu, D.; Piggins, H.D.; Wu, M.S. The Kidney Clock Contributes to Timekeeping by the Master Circadian Clock. Int. J. Mol. Sci. 2019, 20, 2765.
  46. Sinturel, F.; Gos, P.; Petrenko, V.; Hagedorn, C.; Kreppel, F.; Storch, K.F.; Knutti, D.; Liani, A.; Weitz, C.; Emmenegger, Y.; et al. Circadian hepatocyte clocks keep synchrony in the absence of a master pacemaker in the suprachiasmatic nucleus or other extrahepatic clocks. Genes Dev. 2021, 35, 329–334.
  47. Bano-Otalora, B.; Piggins, H.D. Contributions of the lateral habenula to circadian timekeeping. Pharm. Biochem. Behav. 2017, 162, 46–54.
  48. Van Drunen, R.; Eckel-Mahan, K. Circadian Rhythms of the Hypothalamus: From Function to Physiology. Clocks Sleep 2021, 3, 189–226.
  49. Finger, A.M.; Kramer, A. Peripheral clocks tick independently of their master. Genes Dev. 2021, 35, 304–306.
  50. Brum, M.C.B.; Dantas Filho, F.F.; Schnorr, C.C.; Bertoletti, O.A.; Bottega, G.B.; da Costa Rodrigues, T. Night shift work, short sleep and obesity. Diabetol. Metab. Syndr. 2020, 12, 13.
  51. Pariollaud, M.; Lamia, K.A. Cancer in the Fourth Dimension: What Is the Impact of Circadian Disruption? Cancer Discov. 2020, 10, 1455–1464.
  52. Straif, K.; Baan, R.; Grosse, Y.; Secretan, B.; El Ghissassi, F.; Bouvard, V.; Altieri, A.; Benbrahim-Tallaa, L.; Cogliano, V. Carcinogenicity of shift-work, painting, and fire-fighting. Lancet Oncol. 2007, 8, 1065–1066.
  53. Ward, E.M.; Germolec, D.; Kogevinas, M.; McCormick, D.; Vermeulen, R.; Anisimov, V.N.; Aronson, K.J.; Bhatti, P.; Cocco, P.; Costa, G.; et al. Carcinogenicity of night shift work. Lancet Oncol. 2019, 20, 1058–1059.
  54. Blask, D.E.; Dauchy, R.T.; Dauchy, E.M.; Mao, L.; Hill, S.M.; Greene, M.W.; Belancio, V.P.; Sauer, L.A.; Davidson, L. Light exposure at night disrupts host/cancer circadian regulatory dynamics: Impact on the Warburg effect, lipid signaling and tumor growth prevention. PLoS ONE 2014, 9, e102776.
  55. Lauren, S.; Chen, Y.; Friel, C.; Chang, B.P.; Shechter, A. Free-Living Sleep, Food Intake, and Physical Activity in Night and Morning Shift Workers. J. Am. Coll. Nutr. 2020, 39, 450–456.
  56. Agorastos, A.; Nicolaides, N.C.; Bozikas, V.P.; Chrousos, G.P.; Pervanidou, P. Multilevel Interactions of Stress and Circadian System: Implications for Traumatic Stress. Front. Psychiatry 2019, 10, 1003.
  57. Kogevinas, M.; Espinosa, A.; Castello, A.; Gomez-Acebo, I.; Guevara, M.; Martin, V.; Amiano, P.; Alguacil, J.; Peiro, R.; Moreno, V.; et al. Effect of mistimed eating patterns on breast and prostate cancer risk (MCC-Spain Study). Int. J. Cancer 2018, 143, 2380–2389.
  58. Gaucher, J.; Montellier, E.; Sassone-Corsi, P. Molecular Cogs: Interplay between Circadian Clock and Cell Cycle. Trends Cell Biol. 2018, 28, 368–379.
  59. Farshadi, E.; van der Horst, G.T.J.; Chaves, I. Molecular Links between the Circadian Clock and the Cell Cycle. J. Mol. Biol. 2020, 432, 3515–3524.
  60. 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 2002, 111, 41–50.
  61. Matsuo, T.; Yamaguchi, S.; Mitsui, S.; Emi, A.; Shimoda, F.; Okamura, H. Control mechanism of the circadian clock for timing of cell division in vivo. Science 2003, 302, 255–259.
  62. Granda, T.G.; Liu, X.H.; Smaaland, R.; Cermakian, N.; Filipski, E.; Sassone-Corsi, P.; Levi, F. Circadian regulation of cell cycle and apoptosis proteins in mouse bone marrow and tumor. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2005, 19, 304–306.
  63. Sotak, M.; Sumova, A.; Pacha, J. Cross-talk between the circadian clock and the cell cycle in cancer. Ann. Med. 2014, 46, 221–232.
  64. Sancar, A.; Lindsey-Boltz, L.A.; Kang, T.H.; Reardon, J.T.; Lee, J.H.; Ozturk, N. Circadian clock control of the cellular response to DNA damage. FEBS Lett. 2010, 584, 2618–2625.
  65. Antoch, M.P.; Kondratov, R.V.; Takahashi, J.S. Circadian clock genes as modulators of sensitivity to genotoxic stress. Cell Cycle 2005, 4, 901–907.
  66. Gauger, M.A.; Sancar, A. Cryptochrome, circadian cycle, cell cycle checkpoints, and cancer. Cancer Res. 2005, 65, 6828–6834.
  67. Gaddameedhi, S.; Reardon, J.T.; Ye, R.; Ozturk, N.; Sancar, A. Effect of circadian clock mutations on DNA damage response in mammalian cells. Cell Cycle 2012, 11, 3481–3491.
  68. Gorbacheva, V.Y.; Kondratov, R.V.; Zhang, R.; Cherukuri, S.; Gudkov, A.V.; Takahashi, J.S.; Antoch, M.P. Circadian sensitivity to the chemotherapeutic agent cyclophosphamide depends on the functional status of the CLOCK/BMAL1 transactivation complex. Proc. Natl. Acad. Sci. USA 2005, 102, 3407–3412.
  69. Kang, T.H.; Reardon, J.T.; Kemp, M.; Sancar, A. Circadian oscillation of nucleotide excision repair in mammalian brain. Proc. Natl. Acad. Sci. USA 2009, 106, 2864–2867.
  70. Kang, T.H.; Lindsey-Boltz, L.A.; Reardon, J.T.; Sancar, A. Circadian control of XPA and excision repair of cisplatin-DNA damage by cryptochrome and HERC2 ubiquitin ligase. Proc. Natl. Acad. Sci. USA 2010, 107, 4890–4895.
  71. Taniguchi, H.; Fernandez, A.F.; Setien, F.; Ropero, S.; Ballestar, E.; Villanueva, A.; Yamamoto, H.; Imai, K.; Shinomura, Y.; Esteller, M. Epigenetic inactivation of the circadian clock gene BMAL1 in hematologic malignancies. Cancer Res. 2009, 69, 8447–8454.
  72. Zhang, Y.; Devocelle, A.; Souza, L.; Foudi, A.; Tenreira Bento, S.; Desterke, C.; Sherrard, R.; Ballesta, A.; Adam, R.; Giron-Michel, J.; et al. BMAL1 knockdown triggers different colon carcinoma cell fates by altering the delicate equilibrium between AKT/mTOR and P53/P21 pathways. Aging 2020, 12, 8067–8083.
  73. Jiang, W.; Zhao, S.; Jiang, X.; Zhang, E.; Hu, G.; Hu, B.; Zheng, P.; Xiao, J.; Lu, Z.; Lu, Y.; et al. The circadian clock gene Bmal1 acts as a potential anti-oncogene in pancreatic cancer by activating the p53 tumor suppressor pathway. Cancer Lett. 2016, 371, 314–325.
  74. Tang, Q.; Cheng, B.; Xie, M.; Chen, Y.; Zhao, J.; Zhou, X.; Chen, L. Circadian Clock Gene Bmal1 Inhibits Tumorigenesis and Increases Paclitaxel Sensitivity in Tongue Squamous Cell Carcinoma. Cancer Res. 2017, 77, 532–544.
  75. Korkmaz, T.; Aygenli, F.; Emisoglu, H.; Ozcelik, G.; Canturk, A.; Yilmaz, S.; Ozturk, N. Opposite Carcinogenic Effects of Circadian Clock Gene BMAL1. Sci. Rep. 2018, 8, 16023.
  76. Fekry, B.; Ribas-Latre, A.; Baumgartner, C.; Deans, J.R.; Kwok, C.; Patel, P.; Fu, L.; Berdeaux, R.; Sun, K.; Kolonin, M.G.; et al. Incompatibility of the circadian protein BMAL1 and HNF4alpha in hepatocellular carcinoma. Nat. Commun. 2018, 9, 4349.
  77. Peng, H.; Zhang, J.; Zhang, P.P.; Chen, L.; Tang, L.L.; Yang, X.J.; He, Q.M.; Wen, X.; Sun, Y.; Liu, N.; et al. ARNTL hypermethylation promotes tumorigenesis and inhibits cisplatin sensitivity by activating CDK5 transcription in nasopharyngeal carcinoma. J. Exp. Clin. Cancer Res. 2019, 38, 11.
  78. Gwon, D.H.; Lee, W.Y.; Shin, N.; Kim, S.I.; Jeong, K.; Lee, W.H.; Kim, D.W.; Hong, J.; Lee, S.Y. BMAL1 Suppresses Proliferation, Migration, and Invasion of U87MG Cells by Downregulating Cyclin B1, Phospho-AKT, and Metalloproteinase-9. Int. J. Mol. Sci. 2020, 21, 2352.
  79. Sakamoto, W.; Takenoshita, S. Overexpression of Both Clock and Bmal1 Inhibits Entry to S Phase in Human Colon Cancer Cells. Fukushima J. Med. Sci. 2015, 61, 111–124.
  80. Hua, H.; Wang, Y.; Wan, C.; Liu, Y.; Zhu, B.; Yang, C.; Wang, X.; Wang, Z.; Cornelissen-Guillaume, G.; Halberg, F. Circadian gene mPer2 overexpression induces cancer cell apoptosis. Cancer Sci. 2006, 97, 589–596.
  81. Oda, A.; Katayose, Y.; Yabuuchi, S.; Yamamoto, K.; Mizuma, M.; Shirasou, S.; Onogawa, T.; Ohtsuka, H.; Yoshida, H.; Hayashi, H.; et al. Clock gene mouse period2 overexpression inhibits growth of human pancreatic cancer cells and has synergistic effect with cisplatin. Anticancer Res. 2009, 29, 1201–1209.
  82. Hanoun, M.; Eisele, L.; Suzuki, M.; Greally, J.M.; Huttmann, A.; Aydin, S.; Scholtysik, R.; Klein-Hitpass, L.; Duhrsen, U.; Durig, J. Epigenetic silencing of the circadian clock gene CRY1 is associated with an indolent clinical course in chronic lymphocytic leukemia. PLoS ONE 2012, 7, e34347.
  83. Sun, C.M.; Huang, S.F.; Zeng, J.M.; Liu, D.B.; Xiao, Q.; Tian, W.J.; Zhu, X.D.; Huang, Z.G.; Feng, W.L. Per2 inhibits k562 leukemia cell growth in vitro and in vivo through cell cycle arrest and apoptosis induction. Pathol. Oncol. Res. 2010, 16, 403–411.
  84. Zhanfeng, N.; Chengquan, W.; Hechun, X.; Jun, W.; Lijian, Z.; Dede, M.; Wenbin, L.; Lei, Y. Period2 downregulation inhibits glioma cell apoptosis by activating the MDM2-TP53 pathway. Oncotarget 2016, 7, 27350–27362.
  85. Wang, Z.; Li, F.; Wei, M.; Zhang, S.; Wang, T. Circadian Clock Protein PERIOD2 Suppresses the PI3K/Akt Pathway and Promotes Cisplatin Sensitivity in Ovarian Cancer. Cancer Manag. Res. 2020, 12, 11897–11908.
  86. Gong, X.; Tang, H.; Yang, K. PER1 suppresses glycolysis and cell proliferation in oral squamous cell carcinoma via the PER1/RACK1/PI3K signaling complex. Cell Death Dis. 2021, 12, 276.
  87. Nirvani, M.; Khuu, C.; Utheim, T.P.; Sand, L.P.; Sehic, A. Circadian clock and oral cancer. Mol. Clin. Oncol. 2018, 8, 219–226.
  88. Chan, A.B.; Huber, A.L.; Lamia, K.A. Cryptochromes modulate E2F family transcription factors. Sci. Rep. 2020, 10, 4077.
  89. Ye, Y.; Xiang, Y.; Ozguc, F.M.; Kim, Y.; Liu, C.J.; Park, P.K.; Hu, Q.; Diao, L.; Lou, Y.; Lin, C.; et al. The Genomic Landscape and Pharmacogenomic Interactions of Clock Genes in Cancer Chronotherapy. Cell Syst. 2018, 6, 314–328 e2.
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