hnRNPC promotes oral squamous cell carcinoma progression via N6-methyladenosine-dependent stabilization of BCAT1 to enhance branched-chain amino acid metabolism
Abstract
Oral squamous cell carcinoma (OSCC) remains a major cause of cancer-associated mortality worldwide, with current treatments limited by chemoresistance and long-term toxicities. N6-methyladenosine (m6A) modification regulates mRNA fate to drive cancer progression. However, how m6A modification regulates OSCC progression remains to be elucidated. The present study integrated bioinformatics analysis of The Cancer Genome Atlas and Genotype-Tissue Expression datasets and experimental validation to explore the role of heterogeneous nuclear ribonucleoprotein C (hnRNPC), an m6A-associated RNA-binding protein, in OSCC. Bioinformatics analysis of 515 patients with head and neck squamous cell carcinoma (HNSCC) suggested that hnRNPC may have prognostic relevance in HNSCC. High hnRNPC expression associated with advanced pathological stages, poor overall survival and served as a potential risk factor for HNSCC. Functional experiments demonstrated that hnRNPC knockdown in OSCC cell lines inhibited cell proliferation, colony formation, tumor sphere formation and in vivo tumor growth, while downregulating stemness-associated genes (Oct4, Sox2 and Nanog). Mechanistically, hnRNPC promoted branched-chain amino acid (BCAA) metabolism in OSCC. High hnRNPC expression was associated with activated BCAA metabolic pathways and hnRNPC knockdown reduced BCAA uptake, glutamate levels, oxygen consumption rate and glutathione levels. Furthermore, hnRNPC stabilized BCCAA transaminase 1 (BCAT1) mRNA in an m6A-dependent manner. BCAT1 inhibition via ERG240 enhanced the tumor-suppressive effects of hnRNPC knockdown. Exogenous supplementation of α-ketoglutarate rescued energy deficiency and functional defects in hnRNPC-knockdown OSCC cells. Collectively, the present study findings revealed a novel mechanism driving OSCC progression. In this mechanism, hnRNPC regulates BCAA metabolism by stabilizing BCAT1 mRNA in an m6A-dependent manner. The present study supports the prognostic relevance of hnRNPC and may offer a promising therapeutic direction in improving OSCC treatment outcomes by disrupting tumor-specific metabolic and epigenetic adaptations.