Abstract
Abstract
Dysregulation of cholesterol homeostasis is closely associated with the development of various cancers, but the underlying mechanisms remain unclear. This study found that the circadian clock gene Period 2 (PER2) is downregulated in oral squamous cell carcinoma (OSCC), promoting intracellular cholesterol synthesis and cell proliferation. Conversely, PER2 overexpression inhibits cell proliferation by suppressing intracellular cholesterol synthesis. Mechanistically, PER2 binds to Myosin Heavy Chain 9 (MYH9) and recruits Tripartite Motif Containing-21 (TRIM21) to promote ubiquitin-dependent degradation of MYH9, thereby inhibiting the cholesterol synthesis rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), reducing intracellular cholesterol synthesis, and suppressing OSCC proliferation. In OSCC xenograft models, overexpression of PER2 or treatment with the HMGCR inhibitor simvastatin significantly inhibited OSCC growth, with the combination showing markedly enhanced anti-OSCC efficacy compared to either approach alone. To explore the circadian regulatory role of PER2, overexpression or silencing experiments in OSCC demonstrated that PER2 modulates the circadian rhythms of HMGCR expression, intracellular cholesterol, and cell proliferation. Further investigations in subcutaneous OSCC mouse models revealed sex-specific circadian rhythms in PER2 and HMGCR expression, intracellular cholesterol, cell proliferation, and tumor growth in OSCC cells. Specifically, the acrophases of these indicators in OSCC of male mice were delayed relative to females, and the mesors of HMGCR expression, intracellular cholesterol, and cell proliferation were significantly higher than in females. The anticancer efficacy of simvastatin against OSCC in mice varied up to 2.5-fold across six different time points within 24 h, with broader time windows for optimal therapeutic efficacy and adverse effects in female mice than in males. This study identified a novel mechanism by which PER2 reprograms intracellular cholesterol, demonstrating that PER2 upregulation combined with simvastatin represents a potential novel strategy to improve the prognosis of OSCC patients, and clarifies that the anti-OSCC effect of simvastatin exhibits time-dependent and sex differences.