TM-06 * MYC AND MYCN DISRUPTION OF THE MOLECULAR CLOCK IN CANCER CELLS

Abstract

Cancer cells are known to have a metabolic advantage, but it is not known whether the circadian clock, which couples metabolic and cell cycles, restrains cancer cell metabolism and growth. We report that the deregulated expression of the MYC or MYCN oncogene disrupts the molecular clock by inducing NR1D1 (Rev-erbα) to diminish expression and dampen oscillation of ARNTL (Bmal1) that could be rescued by knockdown of Rev-erb. The expression of Rev-erbα is highly correlated with MYC expression in human B cell lymphoma, human T-cell acute lymphoblastic leukemia, murine hepatocellular carcinoma cells and human neuroblastoma cells. MYC or MYCN directly upregulates Rev-erbα expression by binding to its promoter. Suppression of Rev-erbα diminished hepatocellular cancer cell growth, illustrating Rev-erbα's role in MYC-induced tumorigenesis. Furthermore, Rev-erbα expression is a predictor of poor clinical outcome for human neuroblastoma and correlates with MYCN expression. Our results demonstrate an unsuspected link between oncogenic transformation and circadian arrhythmia, which may be metabolically advantageous for cancer cells. Having observed that Myc and N-Myc disrupt circadian rhythm in tumor cells, suggesting a therapeutic opportunity could exist in the window between circadian regulation of the ebb-and-flow of normal cell metabolism and the sustained, not oscillate non-circadian cancer metabolism. The understanding of these basic mechanisms from our work should lead to better cancer treatment strategies that reduce side effects and increase effectiveness.