Citation: Lee Y, Lahens NF, Zhang S, Bedont J, Field JM, Sehgal A (2019) G1/S cell cycle regulators mediate effects of circadian dysregulation on tumor growth and provide targets for timed anticancer treatment. PLoS Biol 17(4): e3000228. https://doi.org/10.1371/journal.pbio.3000228
Circadian disruption has multiple pathological consequences, but the underlying mechanisms are largely unknown. To address such mechanisms, we subjected transformed cultured cells to chronic circadian desynchrony (CCD), mimicking a chronic jet-lag scheme, and assayed a range of cellular functions. The results indicated a specific circadian clock–dependent increase in cell proliferation. Transcriptome analysis revealed up-regulation of G1/S phase transition genes (myelocytomatosis oncogene cellular homolog [Myc], cyclin D1/3, chromatin licensing and DNA replication factor 1 [Cdt1]), concomitant with increased phosphorylation of the retinoblastoma (RB) protein by cyclin-dependent kinase (CDK) 4/6 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. Consistent with circadian regulation, a CDK4/6 inhibitor approved for cancer treatment reduced growth of cultured cells and mouse tumors in a time-of-day–specific manner. Our study identifies a mechanism that underlies effects of circadian disruption on tumor growth and underscores the use of treatment timed to endogenous circadian rhythms.
Circadian misalignment caused by altered sleep–wake cycles, shift work, or frequent jet lag increases susceptibility to several disorders, including cancer. However, the mechanisms by which circadian disruption contributes to disease are not well understood, and so we addressed this issue by investigating the molecular, cellular, and biochemical consequences of chronic circadian desynchronization. Our studies using cancer cell or tumor tissue models show that chronic circadian desynchronization induces multiple oncogenic pathways to promote cell proliferation. In particular, chronic circadian desynchronization promotes phosphorylation of the retinoblastoma (RB) protein, thereby favoring G1/S phase cell cycle progression. Consistent with these findings, the antiproliferative activity of a selective inhibitor of the enzyme that phosphorylates RB has time-of-day–specific effects on cancer cells and mouse tumors, but this time dependence is abrogated by chronic jet-lag conditions. These data suggest a circadian regulation of G1/S cell cycle progression and provide an important molecular rationale for time-of-day–specific treatment of cancer patients, also known as chronotherapy.