Circadian rhythm and its role in malignancy

Abstract

Circadian rhythms are daily oscillations of multiple biological processes directed by endogenous clocks. The circadian timing system comprises peripheral oscillators located in most tissues of the body and a central pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Circadian genes and the proteins produced by these genes constitute the molecular components of the circadian oscillator which form positive/negative feedback loops and generate circadian rhythms. The circadian regulation extends beyond clock genes to involve various clock-controlled genes (CCGs) including various cell cycle genes. Aberrant expression of circadian clock genes could have important consequences on the transactivation of downstream targets that control the cell cycle and on the ability of cells to undergo apoptosis. This may lead to genomic instability and accelerated cellular proliferation potentially promoting carcinogenesis. Different lines of evidence in mice and humans suggest that cancer may be a circadian-related disorder. The genetic or functional disruption of the molecular circadian clock has been found in various cancers including breast, ovarian, endometrial, prostate and hematological cancers. The acquisition of current data in circadian clock mechanism may help chronotherapy, which takes into consideration the biological time to improve treatments by devising new therapeutic approaches for treating circadian-related disorders, especially cancer.

Figure 1

Schematic representation of the mammalian circadian clock mechanism. ROREs are retinoic acid-related orphan nuclear receptor response elements present in Bmal1 promoter to which REV-ERBs and RORs compete to bind whereas E-boxes are regulatory enhancer sequences present in the promoter regions of the genes under consideration to which CLOCK-BMAL1 heterodimer binds. Casein kinase (CK) isoforms phosphorylate PER, CRY and BMAL1 proteins decreasing their stability and critically regulating the time of action of clock proteins. Similarly, targets of GSK3 (glycogen synthase kinase-3) include PER, REV-ERBα and CRY2. c-Myc, Wee1 and Cyclin D1 are clock-controlled cell cycle genes.