Circadian clocks, epigenetics, and cancer

Abstract

Purpose of review: The interplay between circadian rhythm and cancer has been suggested for more than a decade based on the observations that shift work and cancer incidence are linked. Accumulating evidence implicates the circadian clock in cancer survival and proliferation pathways. At the molecular level, multiple control mechanisms have been proposed to link circadian transcription and cell-cycle control to tumorigenesis.

Recent findings: The circadian gating of the cell cycle and subsequent control of cell proliferation is an area of active investigation. Moreover, the circadian clock is a transcriptional system that is intricately regulated at the epigenetic level. Interestingly, the epigenetic landscape at the level of histone modifications, DNA methylation, and small regulatory RNAs are differentially controlled in cancer cells. This concept raises the possibility that epigenetic control is a common thread linking the clock with cancer, though little scientific evidence is known to date.

Summary: This review focuses on the link between circadian clock and cancer, and speculates on the possible connections at the epigenetic level that could further link the circadian clock to tumor initiation or progression.

FIGURE 1

Circadian epigenome and cell-cycle regulation in cancer. Schematic representation of the core clock machinery is shown. The activating heterodimer CLOCK:BMAL1 binds to the E-box elements on the genome, controlling a large number of genes. CLOCK:BMAL1 action is counteracted by the PER and CRY repressor proteins. Additional regulators and chromatin remodelers contribute to circadian gene expression. Among the genes controlled by the clock, a number of them are key cell-cycle regulators. The molecular clock has also been shown to interplay with oncogenes and tumor suppressor genes. CRY, Cryptochrome; MLL, mixed lineage leukemia; PER, Period.