Cancer in the Fourth Dimension: What Is the Impact of Circadian Disruption?

Abstract

Circadian rhythms integrate many physiological pathways, helping organisms to align the timing of various internal processes to daily cycles in the external environment. Disrupted circadian rhythmicity is a prominent feature of modern society, and has been designated as a probable carcinogen. Here, we review multiple studies, in humans and animal models, that suggest a causal effect between circadian disruption and increased risk of cancer. We also discuss the complexity of this connection, which may depend on the cellular context. SIGNIFICANCE: Accumulating evidence points to an adverse effect of circadian disruption on cancer incidence and progression, indicating that time of day could influence the effectiveness of interventions targeting cancer prevention and management.

Figure 1:. Molecular basis of circadian clock disruption and its effect on cancer.

(A) Circadian clock molecular machinery and its direct regulation of cancer related factors. The mammalian clock machinery consists of the positive transcriptional elements CLOCK, or its paralog NPAS2, and BMAL1. This heterodimer activates Periods (Per1–3), Cryptochromes (Cry1, Cry2) and other clock-controlled genes (CCGs) via E-boxes. Notably, key cell cycle regulators such as Wee1 and p21 are CCGs. PER and CRY proteins accumulate in the cytoplasm, and dimerize to form a complex that migrates into the nucleus to repress CLOCK:BMAL1 transcriptional activity. This leads to repression of Pers, Crys, and CCGs, thus forming a negative feedback loop. This cycle takes about 24 hours and is re-initiated by degradation of PERs and CRYs. An additional feedback loop is interlaced with this core loop. Rev-Erbα and Rev-Erbβ (a.k.a. Nuclear receptor subfamily 1, group D members 1 and 2, or Nr1d1 and Nr1d2) and Rors (RAR-related orphan receptors), are CCGs and repress or activate transcription of Bmal1 respectively. PERs and CRYs modulate post-translational regulation of key factors of cell cycle control. (B) Misalignment with the external environment causing circadian disruption of the molecular clock and its cancer-related targets. When lifestyles are aligned with the natural solar day, circadian rhythms allow homeostatic regulation of pathways involved in cell protection (left). When chronically shifting phase from the natural solar day, circadian rhythms of the key clock factors are dampened, affecting regulation of these pathways (right).