hnRNPC Promotes Oral Squamous Cell Carcinoma Progression via m6A-Dependent Stabilization of BCAT1 to Enhance Branched-Chain Amino Acid Metabolism
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Oral squamous cell carcinoma (OSCC) remains a major cause of cancer-related 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 uncharacterized. In this study, we integrated bioinformatics analysis of The Cancer Genome Atlas (TCGA) datasets and experimental validation to explore the role of heterogeneous nuclear ribonucleoprotein C (hnRNPC), an m6A-related RNA-binding protein, in OSCC. Bioinformatics analysis of 515 HNSCC patients identified hnRNPC as a novel independent prognostic biomarker. High hnRNPC expression correlated with advanced pathological stages, poor overall survival, and served as a risk factor for HNSCC. Functional experiments demonstrated that hnRNPC knockdown in OSCC cell lines inhibited cell proliferation, colony formation, tumorsphere formation, and in vivo tumor growth, while downregulating stemness-related genes (OCT4, SOX2, Nanog). Mechanistically, hnRNPC promoted 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 (OCR), and glutathione (GSH) levels. Further, hnRNPC stabilized BCAT1 mRNA in an m6A-dependent manner. BCAT1 inhibition via EGR240 enhanced the tumor-suppressive effects of hnRNPC knockdown. Exogenous supplementation of α-ketoglutarate (α-KG) rescued energy deficiency and functional defects in hnRNPC-knockdown OSCC cells. Collectively, our findings identify a novel hnRNPC/m6A/BCAT1/BCAA metabolism axis driving OSCC progression. This axis not only explains hnRNPC’s prognostic value but also provides a potential therapeutic target for improving OSCC treatment outcomes by disrupting tumor-specific metabolic and epigenetic adaptations.
