The Versatile Role of Period Circadian Regulators (PERs) in Oral Squamous Cell Carcinoma

This review explores the pivotal role of circadian rhythm regulators, particularly the PER genes, in Oral Squamous Cell Carcinoma (OSCC). As key constituents of the biological clock, PERs exhibit a downregulated expression pattern in OSCC, and the expression levels of PERs in OSCC patients are correlated with a favorable prognosis. PERs impact the occurrence and development of OSCC through multiple pathways. In the regulation of cell proliferation, they can function not only through cell cycle regulation but also via metabolic pathways. For example, PER1 can interact with receptors for activated C kinase 1 (RACK1) and phosphatidylinositol 3-kinase (PI3K) through its PAS domain to inhibit glycolysis and thereby reduce cell proliferation. Regarding the regulation of cell death, PERs mediate various types of cell death in OSCC cells, such as p53-dependent apoptosis, protein kinase B (AKT)/mammalian target of rapamycin (mTOR) dependent autophagy, or hypoxia-inducible factor 1-alpha (HIF-1α) mediated ferroptosis. In regulating epithelial-mesenchymal transition (EMT), PERs can lead to the downregulation of EMT-related genes, such as zinc finger E-box binding homeobox 1/2 (ZEB1/2), twist family BHLH transcription factor 1/2 (TWIST1/2), and Vimentin, thereby influencing the migration and invasion capabilities of OSCC cells. In tumor angiogenesis, PERs exert regulatory effects on related factors, such as methionyl aminopeptidase 2 (MetAP2) and vascular endothelial growth factor (VEGF). In the tumor immune microenvironment, PERs can inhibit the inhibitor of kappa B kinase (IKK)/nuclear factor kappa-B (NF-κB) pathway and programmed cell death ligand 1 (PD-L1) expression, thereby enhancing the cytotoxic effect of CD8+ T cells on OSCC cells. In-depth studies focusing on elucidating the precise regulatory mechanisms of PERs can facilitate the development of therapeutic strategies targeting PERs, including restoration of PERs expression/activity, targeting PERs-regulated pathways, combination therapies, and chronotherapy. These furnish a theoretical foundation for formulating individualized treatment plans to achieve precise treatment for patients with OSCC.