Cancer and the Circadian Clock

Abstract

The circadian clock is a master regulator of mammalian physiology, regulating daily oscillations of crucial biological processes and behaviors. Notably, circadian disruption has recently been identified as an independent risk factor for cancer and classified as a carcinogen. As such, it is imperative to discern the underpinning mechanisms by which circadian disruption alters cancer risk. Emergent data, reviewed herein, demonstrate that circadian regulatory functions play critical roles in several hallmarks of cancer, including control of cell proliferation, cell death, DNA repair, and metabolic alteration. Developing a deeper understanding of circadian-cancer regulation cross-talk holds promise for developing new strategies for cancer interception, prevention, and management.

Figure 1.

“Hallmarks” of the circadian clock. The core clock machinery consists of positive (CLOCK and BMAL1) and negative [Cryptochrome (CRY) and Period (PER)] regulators that maintain daily rhythmicity throughout an organism, impacting cell cycle, apoptosis, DNA repair, and metabolic regulation. CLOCK/BMAL1 heterodimers bind to E-box sites to regulate expression of core clock genes (CCGs), including CRY1, CRY2, PER1, PER2, and PER3. CLOCK/BMAL1 also regulates expression of additional clock-controlled genes, such as RORA and Rev-erb, which, in turn, regulate expression of BMAL1 through binding to ROR response elements (RORE). Thus, this autoregulatory network consisting of positive and negative transcription-translation feedback loops confer daily rhythmicity for homeostatic maintenance. The circadian clock influences several biological processes impacting tumor development and progression. Circadian-controlled processes are vast, including cell cycle, apoptosis, metabolic regulation, and DDR, which are all crucial for physiologic homeostasis. Disruption of circadian homeostasis through various factors is associated with increased cancer incidence and is an important, independent risk factor of cancer development in humans.