The diverse roles of the circadian clock in cancer

Abstract

A growing part of the human population is affected by circadian misalignment caused by deregulated sleep, increased nighttime light exposure and erratic eating patterns. Thus, circadian rhythms are a key research area, with compelling links to cancer. Here, we review the circadian regulation of critical cellular processes, including immunity, metabolism, cell cycle control and DNA repair, under physiological homeostasis and in cancer. We discuss the divergent evidence indicating tissue-specific roles of the circadian clock in different cancer types and the potential link between circadian misalignment and early-onset cancers. Finally, we outline how understanding the circadian clock can improve cancer prevention and chronomedicine-based therapies.

Figure 1:. Circadian clock function in normal tissues.

a. Circadian rhythms are coordinated by the central circadian clock, located in the suprachiasmatic nucleus of the hypothalamus. The central clock receives photic cues and transmits endocrine and autonomic signals to synchronize tissue-specific peripheral clocks to the time of day. b. The circadian clock is regulated by a transcriptional/translational feedback loop (TTFL) where CLOCK and BMAL1 drive transcriptional activation through consensus E-Box sequences. During the day, high levels of BMAL1 and CLOCK lead to transcription and subsequent translation of core clock proteins CRY, PER, REV-ERB, and ROR, as well as numerous clock-controlled genes (CCGs). During the night, PER and CRY, translocate into the nucleus to repress the transcriptional activity of the CLOCK- BMAL1 complex.

Figure 2:. Cellular processes regulated by the circadian clock.

The circadian clock is linked to processes that become dysregulated during tumorigenesis including the cell cycle, DNA damage and repair, immunity, and metabolism. a. The circadian clock is implicated in regulating the growth and division of cells as the expression of cyclins regulating the cell cycle is rhythmic, leading to coordination of cell cycle control by the circadian clock. b. Circadian proteins also mediate the DNA damage response and DNA repair. Importantly, the circadian clock exerts its function at the protein-level, with PER2 directly binding to inhibit p53 degradation and CRY2 promoting MYC degradation. c. 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, and the release of cytokines and chemokines is rhythmic, as well as the release of immune cells into the bloodstream. This rhythmic secretion of chemokines facilitates time of day trafficking of immune cells into tissues. d. Lastly, metabolic processes, including glucose and lipid metabolism, are regulated by the circadian clock in a coordinated manner with timing of food intake. Figure created using BioRender.

Figure 3:. The circadian clock as a tumor suppressor or oncogene.

The circadian clock has been shown to have tumor suppressive or tumor promoting functions depending on the specific clock gene or cancer type. a. Knockout of Bmal1 was shown to accelerate Apc LOH and promote the accumulation of myeloid-derived suppressor cells in a mouse model of CRC. Similarly, knockout of either Bmal1 or Per2 promoted Kras-driven lung adenocarcinoma and deletion of Cry2 similarly enhanced MYC-driven lymphoma. b. With regards to the role of the clock as an oncogene, knockout of Bmal1 reduced the formation of cutaneous squamous carcinoma and knockout of Cry1/2 delayed the development of p53-driven lymphoma. In human glioblastoma, downregulation of BMAL1 and CLOCK induced glioblastoma stem cell cycle arrest and apoptosis, whereas upregulation of CLOCK promoted immune suppression. Figure created using BioRender.

Figure 4:. Circadian clock disruption as a driver of colorectal carcinogenesis.

a. CRC is initiated by mutations in the tumor suppressor APC. b. Sequential mutations in known cancer-causing genes including KRAS, p53, and SMAD4 are responsible for driving disease progression. Genetic disruption of the circadian clock, through knockout of Bmal1, has been shown to accelerate CRC progression. An increasing number of studies have also explored the relationship between CRC and circadian clock misalignment through shift work and artificial light-at-night (ALAN). Night shift work in humans has been shown to increase the risk of developing CRC. Concurrently, chronic jet lag, through exposure to ALAN, increases CRC tumor burden in mice. Overall, compelling evidence implicates circadian clock misalignment in CRC carcinogenesis, which suggests that night shift work and ALAN are potential drivers of CRC progression in humans, and especially in early-onset CRC. Figure created using BioRender.