Clock genes: their role in colorectal cancer

Abstract

Clock genes create a complicated molecular time-keeping system consisting of multiple positive and negative feedback loops at transcriptional and translational levels. This circadian system coordinates and regulates multiple cellular procedures implicated in cancer development such as metabolism, cell cycle and DNA damage response. Recent data support that molecules such as CLOCK1, BMAL1 and PER and CRY proteins have various effects on c-Myc/p21 and Wnt/β-catenin pathways and influence multiple steps of DNA damage response playing a critical role in the preservation of genomic integrity in normal and cancer cells. Notably, all these events have already been related to the development and progression of colorectal cancer (CRC). Recent data highlight critical correlations between clock genes' expression and pathogenesis, progression, aggressiveness and prognosis of CRC. Increased expression of positive regulators of this circadian system such as BMAL1 has been related to decrease overall survival while decreased expression of negative regulators such as PER2 and PER3 is connected with poorer differentiation, increased aggressiveness and worse prognosis. The implications of these molecules in DNA repair systems explain their involvement in the development of CRC but at the same time provide us with novel targets for modern therapeutic approaches for patients with advanced CRC.

Keywords: Clock genes; Colorectal cancer; Development; Prognosis.

Figure 1

The molecular mechanism of the cellular circadian system. CLOCK1/BMAL1 and NPAS2/BMAL1 complexes promote the expression of PER and CRY. PER is phosphorylated by CK1ε kinase resulting to its degradation while the accumulation of CRY leads to the formation of PER/CRY/CK1ε complex which inserts to the nucleus and down-regulates the CLOCK1 and BMAL1 activity. Among the transcriptional targets of CLOCK1 and BMAL1 are some cell cycle mediators, tumor suppressor genes and oncogenes regulating cell cycle, cellular metabolism and DNA repair.