Circadian Regulation Of Colon Cancer Stem Cells: Implications For Therapy

The presence of cancer stem cells (CSCs) in colorectal cancer (CRC) has been associated with tumor initiation, metastasis, relapse, and resistance to chemotherapy and radiotherapy. Therefore, a better knowledge of the molecular mechanisms involved in the regulation of CSCs is required to develop treatments that are more effective. Like normal cells, cancer cells contain molecular clocks that generate circadian rhythms in gene expression and metabolic activity. Disruption of circadian rhythms has been linked to increased cancer risk, chemoresistance, and progression in CRC. CSCs also generate rhythms, which could be exploited with a chronopharmacological approach. Although the regulation of the expression of circadian rhythm genes appears to be mediated mainly by transcription-translation feedback loops, the existence of forms of nontranscriptional regulation has been demonstrated. Particularly, microRNAs (miRNA) and SIRT1 are significant players in regulating various aspects of the circadian clock function. Furthermore, miRNA acts as a regulator of cancer progression by regulating the CSC characteristics through SIRT1. These findings led us to hypothesize that there is a circadian rhythm of CSC markers regulated by miRNAs in CRC with SIRT1 acting as a mediator of miRNA activity. The pharmacological regulation of SIRT1, and therefore of the circadian machinery, could result in antiproliferative effects and increased sensitivity to antitumor treatments in CRC.