Circadian rhythm disruption in cancer biology

Abstract

Circadian rhythms show universally a 24-h oscillation pattern in metabolic, physiological and behavioral functions of almost all species. This pattern is due to a fundamental adaptation to the rotation of Earth around its own axis. Molecular mechanisms of generation of circadian rhythms organize a biochemical network in suprachiasmatic nucleus and peripheral tissues, building cell autonomous clock pacemakers. Rhythmicity is observed in transcriptional expression of a wide range of clock-controlled genes that regulate a variety of normal cell functions, such as cell division and proliferation. Desynchrony of this rhythmicity seems to be implicated in several pathologic conditions, including tumorigenesis and progression of cancer. In 2007, the International Agency for Research on Cancer (IARC) categorized "shiftwork that involves circadian disruption [as] probably carcinogenic to humans" (Group 2A in the IARC classification system of carcinogenic potency of an agentagent) (Painting, Firefighting, and Shiftwork; IARC; 2007). This review discusses the potential relation between disruptions of normal circadian rhythms with genetic driving machinery of cancer. Elucidation of the role of clockwork disruption, such as exposure to light at night and sleep disruption, in cancer biology could be important in developing new targeted anticancer therapies, optimizing individualized chronotherapy and modifying lighting environment in workplaces or homes.

Figure 1

A simplified depiction of the mammalian molecular circadian clock machinery. Light perceived by the retina is the most potent synchronizer of the SCN clock. The circadian clock consists of positive and negative autoregulatory feedback loops. The oscillator is composed of interlocking transcription/translational feedback loops, controlling circadian timing. The CLOCK:BMAL1 or CLOCK:NPAS2 heterodimer (positive elements) is the “core loop” and induces E-box–mediated transcription of Per, Cry and Dec; their products are cyclically released in the cytoplasm. When PER and CRY proteins reach a critical concentration, they form heterodimers PER:CRY (negative elements), phosphorylate and translocate into the nucleus, where they inactivate the BMAL1:CLOCK or BMAL1:NPAS2 E-box–mediated transcription, including transcription of their own genes, which reduces their levels sufficiently to allow for the new transcription cycle. In addition, DECs bind to the E-box element of their promoter and inhibit their own transcription directly. CLOCK:BMAL1 also controls the levels of the nuclear receptors retinoid-related orphan receptor α (RORα) and Rev-erbα (known as nuclear receptor subfamily 1, group D, member 1 [NR1D1]), which constitute the “stabilizing/auxiliary loop” by repressing BMAL1 concentration via competitive actions on the retinoic acid–related orphan receptor response element (RORE) (black diamond shape) in the Bmal1 promoter. Cycling of clock components by the core and stabilizing/auxiliary loops also promotes cyclic accumulations of clock-controlled gene (CCG) mRNA species, thus achieving an oscillating pattern and generating rhythmic physiological outputs in a cell type–specific fashion (steroid biosynthesis, cell cycle progression/arrest, cell proliferation, apoptotic pathways, immune function, hormonal oscillations, body temperature, metabolism, DNA repair, response to anticancer drugs and so on). E-boxes (white rectangle shape): regulatory enhancer sequences present in the promoter regions of the genes to which CLOCK:BMAL1 heterodimer binds. Casein kinase (CK) isoforms phosphorylate PER and CRY proteins modulating the nucleocytoplasmic translocation of core clock elements and thereby their transcriptional activity.