Cancer and the Circadian Clock.
Ontology highlight
ABSTRACT:
SUBMITTER: Shafi AA
PROVIDER: S-EPMC8121183 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The circadian clock is a global regulatory system that interfaces with most other regulatory systems and pathways in mammalian organisms. Investigations of the circadian clock-DNA damage response connections have revealed that nucleotide excision repair, DNA damage checkpoints, and apoptosis are appreciably influenced by the clock. Although several epidemiological studies in humans and a limited number of genetic studies in mouse model systems have indicated that clock disruption may predispose mammals to cancer, well-controlled genetic studies in mice have not supported the commonly held view that circadian clock disruption is a cancer risk factor. In fact, in the appropriate genetic background, clock disruption may instead aid in cancer regression by promoting intrinsic and extrinsic apoptosis. Finally, the clock may affect the efficacy of cancer treatment (chronochemotherapy) by modulating the pharmacokinetics and pharmacodynamics of chemotherapeutic drugs as well as the activity of the DNA repair enzymes that repair the DNA damage caused by anticancer drugs.
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Project description:The circadian clock orchestrates global changes in transcriptional regulation on a daily basis via the bHLH-PAS transcription factor CLOCK:BMAL1. Pathways driven by other bHLH-PAS transcription factors have a homologous repressor that modulates activity on a tissue-specific basis, but none have been identified for CLOCK:BMAL1. We show here that the cancer/testis antigen PASD1 fulfills this role to suppress circadian rhythms. PASD1 is evolutionarily related to CLOCK and interacts with the CLOCK:BMAL1 complex to repress transcriptional activation. Expression of PASD1 is restricted to germline tissues in healthy individuals but can be induced in cells of somatic origin upon oncogenic transformation. Reducing PASD1 in human cancer cells significantly increases the amplitude of transcriptional oscillations to generate more robust circadian rhythms. Our results describe a function for a germline-specific protein in regulation of the circadian clock and provide a molecular link from oncogenic transformation to suppression of circadian rhythms.
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Project description:Disruption of the circadian clock is linked to cancer development and progression. Establishing this connection has proven beneficial for understanding cancer pathogenesis, determining prognosis, and uncovering novel therapeutic targets. However, barriers to characterizing the circadian clock in human pancreas and human pancreatic cancer-one of the deadliest malignancies-have hindered an appreciation of its role in this cancer. Here, we employed normalized coefficient of variation (nCV) and clock correlation analysis in human population-level data to determine the functioning of the circadian clock in pancreas cancer and adjacent normal tissue. We found a substantially attenuated clock in the pancreatic cancer tissue. Then we exploited our existing mouse pancreatic transcriptome data to perform an analysis of the human normal and pancreas cancer samples using a machine learning method, cyclic ordering by periodic structure (CYCLOPS). Through CYCLOPS ordering, we confirmed the nCV and clock correlation findings of an intact circadian clock in normal pancreas with robust cycling of several core clock genes. However, in pancreas cancer, there was a loss of rhythmicity of many core clock genes with an inability to effectively order the cancer samples, providing substantive evidence of a dysregulated clock. The implications of clock disruption were further assessed with a Bmal1 knockout pancreas cancer model, which revealed that an arrhythmic clock caused accelerated cancer growth and worse survival, accompanied by chemoresistance and enrichment of key cancer-related pathways. These findings provide strong evidence for clock disruption in human pancreas cancer and demonstrate a link between circadian disruption and pancreas cancer progression.
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Project description:Circadian rhythms are natural rhythms that widely exist in all creatures, and regulate the processes and physiological functions of various biochemical reactions. The circadian clock is critical for cancer occurrence and progression. Its function is regulated by metabolic activities, and the expression and transcription of various genes. This review summarizes the composition of the circadian clock; the biological basis for its function; its relationship with, and mechanisms in, cancer; its various functions in different cancers; the effects of anti-tumor treatment; and potential therapeutic targets. Research in this area is expected to advance understanding of circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like protein 1 (BMAL1) in tumor diseases, and contribute to the development of new anti-tumor treatment strategies.
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Project description:Circadian genes may be involved in regulating cancer-related pathways, including cell proliferation, DNA damage response, and apoptosis. We aimed to assess the role of genetic variation in core circadian rhythm genes with the risk of fatal prostate cancer and first morning void urinary 6-sulfatoxymelatonin levels.We used unconditional logistic regression to evaluate the association of 96 single-nucleotide polymorphisms (SNPs) across 12 circadian-related genes with fatal prostate cancer in the AGES-Reykjavik cohort (n = 24 cases), the Health Professionals Follow-Up Study (HPFS) (n = 40 cases), and the Physicians' Health Study (PHS) (n = 105 cases). We used linear regression to evaluate the association between SNPs and first morning void urinary 6-sulfatoxymelatonin levels in AGES-Reykjavik. We used a kernel machine test to evaluate whether multimarker SNP sets in the pathway (gene based) were associated with our outcomes.None of the individual SNPs were consistently associated with fatal prostate cancer across the three cohorts. In each cohort, gene-based analyses showed that variation in the CRY1 gene was nominally associated with fatal prostate cancer (p values = 0.01, 0.01, and 0.05 for AGES-Reykjavik, HPFS, and PHS, respectively). In AGES-Reykjavik, SNPs in TIMELESS (four SNPs), NPAS2 (six SNPs), PER3 (two SNPs) and CSNK1E (one SNP) were nominally associated with 6-sulfatoxymelatonin levels.We did not find a strong and consistent association between variation in core circadian clock genes and fatal prostate cancer risk, but observed nominally significant gene-based associations with fatal prostate cancer and 6-sulfatoxymelatonin levels.
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Project description:Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARγ, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock.
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Project description:Circadian clocks constitute the evolutionary molecular machinery that dictates the temporal regulation of physiology to maintain homeostasis. Disruption of the circadian rhythm plays a key role in tumorigenesis and facilitates the establishment of cancer hallmarks. Conversely, oncogenic processes directly weaken circadian rhythms. Pharmacological modulation of core clock genes is a new approach in cancer therapy. The integration of circadian biology into cancer research offers new options for making cancer treatment more effective, encompassing the prevention, diagnosis, and treatment of this devastating disease. This review highlights the role of the circadian clock in tumorigenesis and cancer hallmarks, and discusses how pharmacological modulation of circadian clock genes can lead to new therapeutic options.
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Project description:The MYC oncogene encodes MYC, a transcription factor that binds the genome through sites termed E-boxes (5'-CACGTG-3'), which are identical to the binding sites of the heterodimeric CLOCK-BMAL1 master circadian transcription factor. Hence, we hypothesized that ectopic MYC expression perturbs the clock by deregulating E-box-driven components of the circadian network in cancer cells. We report here that deregulated expression of MYC or N-MYC disrupts the molecular clock in vitro by directly inducing REV-ERBα to dampen expression and oscillation of BMAL1, and this could be rescued by knockdown of REV-ERB. REV-ERBα expression predicts poor clinical outcome for N-MYC-driven human neuroblastomas that have diminished BMAL1 expression, and re-expression of ectopic BMAL1 in neuroblastoma cell lines suppresses their clonogenicity. Further, ectopic MYC profoundly alters oscillation of glucose metabolism and perturbs glutaminolysis. Our results demonstrate an unsuspected link between oncogenic transformation and circadian and metabolic dysrhythmia, which we surmise to be advantageous for cancer.
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Project description:The circadian clock governs activity of many physiological processes, thereby playing a pivotal role in human health. Circadian disruption is closely associated with cancer development; in particular, recent discoveries have provided strong evidence supporting specific functions of different molecular clock components in either promoting or inhibiting tumorigenesis. This narrative review aims to summarize the existing data on molecular connections between the clock and cancer. These results along with future efforts pave the road to targeting the circadian clock as a novel pathway for therapeutic intervention. Given the implications of chrono-nutrition interventions such as time-restricted feeding in extending lifespan, chrono-nutrition may have preventive and therapeutic applications for individuals with and at-risk of age-related diseases including cancer.
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Project description:Circadian rhythms regulate many physiological and behavioral processes, including sleep, metabolism and cell division, which have a 24-h oscillation pattern. Rhythmicity is generated by a transcriptional-translational feedback loop in individual cells, which are synchronized by the central pacemaker in the brain and external cues. Epidemiological and clinical studies indicate that disruption of these rhythms can increase both tumorigenesis and cancer progression. Environmental changes (shift work, jet lag, exposure to light at night), mutations in circadian regulating genes, and changes to clock gene expression are recognized forms of disruption and are associated with cancer risk and/or cancer progression. Experimental data in animals and cell cultures further supports the role of the cellular circadian clock in coordinating cell division and DNA repair, and disrupted cellular clocks accelerate cancer cell growth. This review will summarize studies linking circadian disruption to cancer biology and explore how such disruptions may be further altered by common characteristics of tumors including hypoxia and acidosis. We will highlight how circadian rhythms might be exploited for cancer drug development, including how delivery of current chemotherapies may be enhanced using chronotherapy. Understanding the role of circadian rhythms in carcinogenesis and tumor progression will enable us to better understand causes of cancer and how to treat them.
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