pubmed.ncbi.nlm.nih.gov

Circadian clocks in health and disease: Dissecting the roles of the biological pacemaker in cancer - PubMed

  • ️Sun Jan 01 2023

Review

Circadian clocks in health and disease: Dissecting the roles of the biological pacemaker in cancer

Bridget M Fortin et al. F1000Res. 2023.

Abstract

In modern society, there is a growing population affected by circadian clock disruption through night shift work, artificial light-at-night exposure, and erratic eating patterns. Concurrently, the rate of cancer incidence in individuals under the age of 50 is increasing at an alarming rate, and though the precise risk factors remain undefined, the potential links between circadian clock deregulation and young-onset cancers is compelling. To explore the complex biological functions of the clock, this review will first provide a framework for the mammalian circadian clock in regulating critical cellular processes including cell cycle control, DNA damage response, DNA repair, and immunity under conditions of physiological homeostasis. Additionally, this review will deconvolute the role of the circadian clock in cancer, citing divergent evidence suggesting tissue-specific roles of the biological pacemaker in cancer types such as breast, lung, colorectal, and hepatocellular carcinoma. Recent evidence has emerged regarding the role of the clock in the intestinal epithelium, as well as new insights into how genetic and environmental disruption of the clock is linked with colorectal cancer, and the molecular underpinnings of these findings will be discussed. To place these findings within a context and framework that can be applied towards human health, a focus on how the circadian clock can be leveraged for cancer prevention and chronomedicine-based therapies will be outlined.

Keywords: Wnt signaling; cancer; chronomedicine; chronotherapy; circadian clock; colorectal cancer; early-onset cancer; night shift work.

Copyright: © 2023 Fortin BM et al.

PubMed Disclaimer

Conflict of interest statement

No competing interests were disclosed.

Figures

Figure 1.
Figure 1.. Circadian clock function in normal tissues.

In mammals, circadian rhythms are coordinated by the central circadian clock, located in the suprachiasmatic nucleus (SCN) of the hypothalamus ( Inouye & Kawamura, 1979; Stephan & Zucker, 1972). The central clock receives photic cues and transmits endocrine and autonomic signals to synchronize tissue-specific peripheral clocks to the time of day ( Pando et al., 2002; Welsh et al., 2004, 2010; Whitmore et al., 2000; Yamazaki et al., 2000). The circadian clock is regulated by a TTFL where CLOCK and BMAL1 drive transcriptional activation and PERIOD (PER) and CYPTOCHROME (CRY) feedback to repress this transcriptional activity. This TTFL regulates gene expression programs that modulate critical cellular processes needed to maintain homeostasis including cell division, maintenance of genome integrity, immunity, endocrine and metabolic functions. The circadian clock is implicated in regulating the growth and division of cells as the expression of cyclins is rhythmic ( Graña & Reddy, 1995; Vermeulen et al., 2003). Circadian proteins also mediate the DNA damage response ( Gery et al., 2006; Kang & Leem, 2014) and DNA repair including nucleotide excision repair ( Gaddameedhi et al., 2011; Marteijn et al., 2014), base excision repair ( Kozmin et al., 2005; Krokan & Bjørås, 2013), homologous recombination and non-homologous end-joining ( Cotta-Ramusino et al., 2011; Shafi et al., 2021). Importantly, in addition to its transcriptional regulation, the circadian clock also exerts its function at the protein-level, with PER2 directly binding to inhibit p53 degradation ( Gotoh et al., 2014) and CRY2 promoting MYC degradation ( Huber et al., 2016). In addition to regulation of cell division and DNA damage, the immune system is also tightly regulated by the circadian clock to promote efficient immunologic response to infection. Immune cells have functional circadian clocks ( Keller et al., 2009; Silver et al., 2012) and the release of cytokines and chemokines is rhythmic ( Gibbs et al., 2014; Pariollaud et al., 2018), as well as the release of immune cells into the bloodstream ( Dimitrov et al., 2007; Méndez-Ferrer et al., 2008). This rhythmic secretion of chemokines facilitates time of day trafficking of immune cells into tissues ( Gibbs et al., 2014; Méndez-Ferrer et al., 2008) which has been demonstrated to mediate the host response to infection ( Kiessling et al., 2017) and disease ( Gibbs et al., 2014; Kitchen et al., 2020). Lastly, metabolic processes, including glucose and lipid metabolism, cardiovascular health and endocrine hormone secretion are regulated by the circadian clock ( Green et al., 2008; Verlande & Masri, 2019). Figure created using

BioRender

.

Figure 2.
Figure 2.. Potential roles of circadian clock disruption during tumor initiation and progression.

In normal tissue, the circadian clock maintains homeostasis through diverse functions including control of the cell cycle, genome integrity, immunity, and metabolism. Given the numerous roles of the circadian clock in maintaining physiology, it is not surprising that the clock has been implicated in cancer initiation and progression. Indeed, a large body of evidence has linked the circadian clock to processes that become dysregulated during tumorigenesis including the cell cycle, proliferation, genome stability, stemness, metastasis, inflammation, immunity, and oncogenic signaling pathways. Analyzing over 32 different cancer types, it was found that clock genes are associated with activation or inhibition of oncogenic signaling pathways including phosphatidylinositol 3-kinase (PI3K)/AKT and RAS/mitogen-activated protein kinase (MAPK) signaling pathways ( Ye et al., 2018). Knockout of Bmal1 was shown to accelerate Apc LOH in a mouse model of CRC suggesting that the clock may be involved in maintaining genome integrity ( Chun, Fortin, Fellows et al., 2022). With regards to the role of the clock in the cell cycle, mutation of Cry2 in MYC-transformed fibroblasts suppressed p53 and enhanced growth ( Chan et al., 2021) whereas downregulation of BMAL1 and CLOCK in human glioblastoma stem cells induced cell cycle arrest and apoptosis ( Chen et al., 2020; Dong et al., 2019), demonstrating a cancer and tissue-specific effect of the clock on tumorigenesis. The circadian clock has also been shown to regulate immunity and metastasis as clock gene dysregulation is correlated with increased inflammation ( Gibbs et al., 2014) and T cell exhaustion ( Wu et al., 2019). Chronic jet lag promotes an immunosuppressive microenvironment, enhances stemness, and increases cancer cell metastasis ( Hadadi et al., 2020) and intravasation of circulating breast tumor cells was shown to have time-of-day frequency ( Diamantopoulou et al., 2022) suggesting potential clock-control of metastatic seeding. A direct link between circadian immune function and anti-tumor immunity was demonstrated by clock-dependent trafficking of DCs to the tumor draining lymph node regulating circadian function of tumor-antigen specific CD8s and melanoma volume after engraftment ( Wang et al., 2022). Lastly, the circadian clock has been implicated in metabolic pathways involved in driving cellular proliferation, especially related to the crosstalk between the clock and MYC signaling ( Altman et al., 2015; Chun, Fortin, Fellows et al., 2022; Shostak et al., 2016; Stokes et al., 2021). Figure created using

BioRender

.

Figure 3.
Figure 3.. Circadian clock disruption as a driver of colorectal carcinogenesis.

CRC has been shown to be initiated by sequential mutations in known cancer-causing genes including APC, KRAS, p53, and SMAD4 ( Drost et al., 2015; Li et al., 2014). Numerous studies have found that the circadian clock is involved in CRC initiation and progression. Importantly, circadian clock disruption promotes CRC pathogenesis in multiple mouse models ( Chun, Fortin, Fellows et al., 2022; Stokes et al., 2021; Wood et al., 2008). Additionally, the core clock gene CLOCK was found to be mutated in 53% of CRC that display microsatellite instability and it was shown that CLOCK binds near DNA damage related genes p21, BRCA1 and RAD50 to mediate DNA repair, apoptosis, and cell cycle arrest ( Alhopuro et al., 2010). Loss of Bmal1 in Apc ex1-15/+ mice and intestinal organoids accelerated Apc LOH which drove transformation ( Chun, Fortin, Fellows et al., 2022). These studies implicate the circadian clock in maintenance of genome stability and demonstrate a role for circadian clock disruption in promoting colorectal carcinogenesis. An increasing number of studies have also explored the relationship between CRC and circadian clock disruption through shift work, light-at-night, and diet. Night shift work in humans has been shown to increase the risk of developing CRC ( Papantoniou et al., 2017; Schernhammer et al., 2003) and chronic jet lag, through exposure to light and night, increases CRC tumor burden in mice ( Chun, Fortin, Fellows et al., 2022; Stokes et al., 2021). High-fat diet also disrupts molecular circadian rhythms ( Eckel-Mahan et al., 2013; Hatori et al., 2012; Kohsaka et al., 2007). Given that HFD is known to enhance tumorigenicity of intestinal progenitors ( Beyaz et al., 2016; Mana et al., 2021) and exacerbate CRC ( Goncalves et al., 2019), the potential link with the intestinal clock warrants further investigation. Overall, compelling evidence implicates circadian clock disruption in CRC carcinogenesis, which suggests that night shift work, light-at-night, and diet could be potential drivers of CRC progression in humans, and especially in young-onset CRC. Figure created using

BioRender

.

Similar articles

References

    1. Acosta-Rodríguez V, Rijo-Ferreira F, Izumo M, et al. : Circadian alignment of early onset caloric restriction promotes longevity in male C57BL/6J mice. Science (New York, N.Y.). 2022;376(6598):1192–1202. 10.1126/science.abk0297 - DOI - PMC - PubMed
    1. Åkerstedt T, Knutsson A, Narusyte J, et al. : Night work and breast cancer in women: A Swedish cohort study. BMJ Open. 2015;5(4):e008127. 10.1136/bmjopen-2015-008127 - DOI - PMC - PubMed
    1. Al Bitar S, Gali-Muhtasib H: The role of the cyclin dependent kinase inhibitor p21cip1/waf1 in targeting cancer: Molecular mechanisms and novel therapeutics. Cancers. 2019;11(10). 10.3390/cancers11101475 - DOI - PMC - PubMed
    1. Alhopuro P, Björklund M, Sammalkorpi H, et al. : Mutations in the circadian gene CLOCK in colorectal cancer. Mol. Cancer Res. 2010;8(7):952–960. 10.1158/1541-7786.MCR-10-0086 - DOI - PubMed
    1. Alterman T, Luckhaupt SE, Dahlhamer JM, et al. : Prevalence rates of work organization characteristics among workers in the U.S.: Data from the 2010 National Health Interview Survey. Am. J. Ind. Med. 2013;56(6):647–659. 10.1002/ajim.22108 - DOI - PMC - PubMed

Publication types

MeSH terms

Grants and funding

BMF was supported by the T32 Interdisciplinary Cancer Research (IDCR) Training Program (Grant # T32CA009054). We acknowledge the support of the Chao Family Comprehensive Cancer Center (CFCCC) at the University of California, Irvine, which is supported by the National Institutes of Health (NIH)/National Cancer Institute (NCI) (P30 CA062203). Financial support for the Pannunzio lab was provided by NIH/NCI grant R37CA266042, as well as the American Cancer Society Institutional Research Grant (ACS IRG-16-187-13). Financial support for the Masri laboratory is provided through the NIH/NCI (Grants: R01CA244519 and R01CA259370), the V Foundation for Cancer Research, and Johnson and Johnson.