Circadian Clock, Cell Division, and Cancer: From Molecules to Organism

Shostak, Anton

doi:10.3390/ijms18040873

Cited by 141 publications

(121 citation statements)

References 131 publications

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“…The circadian clock controls diverse cellular processes, including the cell cycle, DNA damage response and apoptosis, by regulating genes, such as p16 , p21 , Cyclin D1 , Wee1 and p53. 38,91–93 These molecular links further support the notion that disruption of circadian regulation promotes cancer phenotypes, such as rapid proliferation, impairment of DNA repair and resistance to apoptosis. Given the potential significance of dedifferentiation processes in carcinogenesis, it is critical to understand the effects of global epigenetic changes on the circadian clock and how the circadian clock is regulated in developing cancer cells (Fig.…”

Section: Impact Of Circadian Clock Disruption On Cancer Developmentsupporting

confidence: 52%

Circadian clock and cancer: From a viewpoint of cellular differentiation

2020

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Abbreviations & Acronyms AML = acute myeloid leukemia ccg = clock-controlled gene DNMT1 = DNA methyltransferase 1 E19 = embryonic day 19 ES = embryonic stem iPS = induced pluripotent stem MEF = mouse embryonic fibroblast MRT = malignant rhabdoid tumor OSKM = Oct3/4, Sox2, Klf4 and c-Myc Per2 Luc = Per2::Luciferase SCN = suprachiasmatic nucleus SMG = submandibular gland TTFL = transcriptionaltranslational feedback loop UPR = unfolded protein response Correspondence: KazuhiroAbstract: The circadian clock controls and adapts diverse physiological and behavioral processes according to Earth's 24-h cycle of environmental changes. The master pacemaker of the mammalian circadian clock resides in the hypothalamic suprachiasmatic nucleus, but almost all cells throughout the body show circadian oscillations in gene expression patterns and associated functions. Recent studies have shown that the circadian clock gradually develops during embryogenesis. Embryonic stem cells and induced pluripotent stem cells do not show circadian oscillations of gene expression, but gradually develop circadian clock oscillation during differentiation; thus, the developmental program of circadian clock emergence appears closely associated with cellular differentiation. Like embryonic stem cells, certain cancer cell types also lack the circadian clock. Given this similarity between embryonic stem cells and cancer cells, interest is growing in the contributions of circadian clock dysfunction to dedifferentiation and cancer development. In this review, we summarize recent advances in our understanding of circadian clock emergence during ontogenesis, and discuss possible associations with cellular differentiation and carcinogenesis. Considering the multiple physiological functions of circadian rhythms, circadian abnormalities might contribute to a host of diseases, including cancer. Insights on circadian function could lead to the identification of biomarkers for cancer diagnosis and prognosis, as well as novel targets for treatment. Hierarchical organization of the mammalian circadian clockMost organisms have evolved an intrinsic circadian clock to adapt physiological functions to the planet's 24-h environmental cycles. In mammals, the circadian clock controls such physiological and behavioral functions as sleep-wake cycles, metabolism, hormonal secretion, body temperature, immune responses and neuronal functions. 1,2 The master pacemaker of the mammalian circadian clock resides in the SCN of the hypothalamus. A subset of SCN neurons receive a clock-resetting light signal from the retinohypothalamic tract and communicate with other SCN cells to maintain robust circadian oscillations of neuronal activity. These neuronal oscillations in turn synchronize other peripheral oscillators throughout the body through neuronal and hormonal signaling pathways. 3,4 At the cellular and molecular levels, the circadian clock is comprised of a set of core clock genes functionally organized into TTFLs that generate cell-autonomous circadian oscillations in gene ex...

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Section: Impact Of Circadian Clock Disruption On Cancer Developmentsupporting

confidence: 52%

Circadian clock and cancer: From a viewpoint of cellular differentiation

2020

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“…As chronic circadian disruption via shift work, increased exposure to light at night, and inadequate daylight exposure become increasingly pervasive in modern society, so have we seen an increase in diseases linked to chronic circadian disruption, such as cancer, obesity, diabetes and cardiovascular and neurodegenerative disease (Evans and Davidson, 2013;Musiek and Holtzman, 2016;Shostak, 2017). Inflammation plays an important part in the pathology of all these diseases, leading many to hypothesize that the dysregulation of immunity plays a major role in the link between chronic circadian disruption and associated diseases.…”

Section: Discussionmentioning

confidence: 99%

Post-Transcriptional Circadian Regulation in Macrophages Organizes Temporally Distinct Immunometabolic States

Collins

Cervantes-Silva

Timmons

et al. 2020

Preprint

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Our core timekeeping mechanism, the circadian clock, regulates an astonishing amount of cellular physiology and behavior, playing a vital role in organismal fitness. While the mechanics of circadian control over cellular regulation can in part be explained by the transcriptional activation stemming from the positive arm of the clock's transcription-translation negative feedback loop, research has shown that extensive circadian regulation occurs beyond transcriptional activation in fungal species and data suggest that this post-transcriptional regulation may also be preserved in mammals. To determine the extent to which circadian output is regulated post-transcriptionally in mammalian cells, we comprehensively profiled the transcriptome and proteome of murine bone marrow-derived macrophages in a high resolution, sample rich time course. We found that only 15% of the circadian proteome had corresponding oscillating mRNA and this regulation was cell intrinsic. Ontological analysis of oscillating proteins revealed robust temporal enrichment for protein degradation and translation, providing potential insights into the source of this extensive posttranscriptional regulation. We noted post-transcriptional temporal-gating across a number of connected metabolic pathways. This temporal metabolic regulation further corresponded with rhythms we observed in ATP production, mitochondrial morphology, and phagocytosis. With the strong interconnection between cellular metabolic states and macrophage phenotypes/responses, our work demonstrates that post-transcriptional circadian regulation in macrophages is broadly utilized as a tool to confer time-dependent immune function and responses. As macrophages coordinate many immunological and inflammatory functions, an understanding of this regulation provides a framework to determine the impact of circadian regulation on a wide array of disease pathologies.

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“…It has long been proposed that disruption of circadian rhythm may contribute to the development of cancer, and shift work involving circadian disruption has been classified as a probable carcinogen to human beings by the International Agency for Research on Cancer . Epidemiological studies have shown that circadian disruption is significantly associated with increased risk of a range of malignancies, such as breast and prostate cancer .…”

Section: Discussionmentioning

confidence: 99%

Functional polymorphisms in circadian positive feedback loop genes predict postsurgical prognosis of gastric cancer

et al. 2019

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Background Circadian positive feedback loop (CPFL) genes (CLOCK, BAML1, and NPAS2) have been implicated in cancer initiation and progression. The purpose of this study was to explore the effects of single‐nucleotide polymorphisms (SNPs) in CPFL genes on prognosis of gastric cancer (GC) patients. Methods Nine functional SNPs from the three CPFL genes were genotyped in a cohort of 704 GC patients undergoing resection. Multivariate Cox regression model and Kaplan‐Meier curve were used for prognosis analysis. Results Among the nine SNPs, rs11133399 in CLOCK, rs1044432 and rs2279284 in BAML1 were significantly associated with GC overall survival and recurrence‐free survival. The unfavorable genotypes of these SNPs showed a cumulative effect on GC prognosis. Multivariate assessment model indicated that these SNPs, in conjunction with clinical variables, enhanced the power to predict GC prognosis. In addition, survival tree analysis revealed the genotype of rs11133399 as a primary risk factor contributing to the prognosis of GC patients. Functional assays showed that the G allele in rs11133399 significantly enhanced luciferase reporter activity than A allele. Immunohistochemical analysis further demonstrated that the genotype of rs11133399 was significantly associated with the expression level of CLOCK in GC tissues, suggesting that this SNP might affect the prognosis of GC through its influence on the expression of CLOCK gene. Conclusions Our data indicate that SNPs in CPFL genes might contribute to the clinical outcome of GC through their impact on gene expression. Further studies are needed to elucidate its underlying molecular mechanisms.

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Circadian Clock, Cell Division, and Cancer: From Molecules to Organism

Cited by 141 publications

References 131 publications

Circadian clock and cancer: From a viewpoint of cellular differentiation

Circadian clock and cancer: From a viewpoint of cellular differentiation

Post-Transcriptional Circadian Regulation in Macrophages Organizes Temporally Distinct Immunometabolic States

Functional polymorphisms in circadian positive feedback loop genes predict postsurgical prognosis of gastric cancer

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