Circadian clock circuitry in colorectal cancer

Abstract

Colorectal cancer is the most prevalent among digestive system cancers. Carcinogenesis relies on disrupted control of cellular processes, such as metabolism, proliferation, DNA damage recognition and repair, and apoptosis. Cell, tissue, organ and body physiology is characterized by periodic fluctuations driven by biological clocks operating through the clock gene machinery. Dysfunction of molecular clockworks and cellular oscillators is involved in tumorigenesis, and altered expression of clock genes has been found in cancer patients. Epidemiological studies have shown that circadian disruption, that is, alteration of bodily temporal organization, is a cancer risk factor, and an increased incidence of colorectal neoplastic disease is reported in shift workers. In this review we describe the involvement of the circadian clock circuitry in colorectal carcinogenesis and the therapeutic strategies addressing temporal deregulation in colorectal cancer.

Keywords: Circadian rhythm; Clock gene; Colorectal cancer.

Figure 1

Biological clock and the cell processes involved in colorectal carcinogenesis. The scheme renders the transcriptional/translational feedback loop through which the molecular clockwork operates, and depicts its interplay with the aryl hydrocarbon receptor (AHR)/ARNT system in the control of the cell cycle and apoptosis, and ultimately in the regulation of the processes of cell proliferation and death, whose deregulation brings about colorectal cancer (CRC) onset and progression. CK: Casein kinase; AHR: Aryl hydrocarbon receptor; PPAR: Peroxisome proliferator-activated receptor; CHK: Checkpoint kinase; ATR: Ataxia telangiectasia and rad3-related; ATM: Ataxia telangiectasia mutated; ARNT: Aryl hydrocarbon receptor nuclear translocator; HLF: Hepatic leukaemia factor; TEF: Thyrotroph embryonic factor.