PRMT1‐Mediated SWI/SNF Complex Recruitment via SMARCC1 Drives IGF2BP2 Transcription to Enhance Carboplatin Resistance in Head and Neck Squamous Cell Carcinoma

Abstract Head and neck squamous cell carcinoma (HNSCC) is a malignancy with poor prognosis and chemotherapy resistance. Here, protein arginine methyltransferase 1 (PRMT1) is identified as a key driver of carboplatin (CBP) resistance in HNSCC. Analyses of clinical samples, cell lines, patient‐derived organoids, and xenograft models reveal that PRMT1 promotes tumor growth and CBP resistance through a novel, methyltransferase‐independent mechanism. Conditional PRMT1 knockout suppresses tumorigenesis and enhances CBP sensitivity in vivo, highlighting its essential role in HNSCC progression. Mechanistically, PRMT1 recruits the SWI/SNF chromatin remodeling complex via direct interaction with SMARCC1, leading to the transcriptional activation of insulin‐like growth factor 2 mRNA‐binding protein 2 (IGF2BP2), which enhances CBP resistance and tumor growth. Notably, this function is independent of PRMT1's enzymatic activity, distinguishing it from its well‐established roles in arginine methylation. Furthermore, pre‐B‐cell leukemia homeobox 2 (PBX2) is identified as an upstream transcriptional activator that binds the PRMT1 promoter, driving its overexpression and reinforcing this oncogenic network. Clinically, high PBX2, PRMT1, SMARCC1, and IGF2BP2 expression correlates with malignant progression and poor prognosis in HNSCC patients. This study uncovers a previously unrecognized non‐catalytic function of PRMT1 and highlights the PBX2‐PRMT1‐SWI/SNF‐IGF2BP2 axis as a potential therapeutic target for overcoming CBP resistance in HNSCC.