Circadian disruption has multiple pathological consequences, but the underlying mechanisms are largely unclear. To address such mechanisms, we subjected cultured cells to chronic circadian desynchrony (CCD), mimicking a chronic jet-lag paradigm, and assayed a range of cellular functions.  The results indicated a specific circadian clock-dependent increase in cell proliferation. Transcriptome analysis revealed upregulation of G1-S-phase transition genes (cMyc, CyclinD1/3, Cdt1), concomitant with increased phosphorylation of the Retinoblastoma protein (Rb) by Cyclin D kinase 4/6 (CDK4/6) and increased G1-S progression. Phospho-Rb (Ser807/811) was found to oscillate in a circadian fashion and exhibit phase-shifted rhythms in circadian desynchronized cells. A CDK4/6 inhibitor approved for cancer treatment reduced growth of cultured cells and mouse tumors in a time-of-day specific manner, but the time dependence was lost with CCD. Our study identifies a mechanism that underlies effects of circadian disruption on tumor growth and underscores the importance of treatment timed to endogenous circadian rhythms. SOURCE: Yool Lee Perelman School of Medicine at the University of Pennsylvania

Pluto Bioinformatics

GSE119668: Molecular mechanism impacted by circadian disruption underscores the importance of timed anti-cancer treatment