Liu Shixian, Zhang Wentao, Liu Weiwei, Ding Zhao, Zhang Ruijing, Han Yuefeng, Niu Zihao, Zhang Mengdie, Li Hui, Li Dapeng, Wang Zixi, Peng Jie, Wu Yu, Han Yanxun, Xie Zihui, Wu Jing, Qin Liang, Hu Zhongdong, Chen Xu, Hu Yunlong, Liu Yehai, Ma Shiyin, Zha Xiaojun
Department of Otolaryngology, Head & Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
Department of Otolaryngology, Head & Neck Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233004, China.
Adv Sci (Weinh). 2025 Jun;12(22):e2417460. doi: 10.1002/advs.202417460. Epub 2025 Apr 24.
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.
头颈部鳞状细胞癌（HNSCC）是一种预后较差且具有化疗耐药性的恶性肿瘤。在此，蛋白精氨酸甲基转移酶1（PRMT1）被确定为HNSCC中顺铂（CBP）耐药的关键驱动因素。对临床样本、细胞系、患者来源的类器官和异种移植模型的分析表明，PRMT1通过一种新的、不依赖甲基转移酶的机制促进肿瘤生长和CBP耐药。条件性PRMT1基因敲除在体内抑制肿瘤发生并增强CBP敏感性，突出了其在HNSCC进展中的重要作用。从机制上讲，PRMT1通过与SMARCC1直接相互作用招募SWI/SNF染色质重塑复合物，导致胰岛素样生长因子2 mRNA结合蛋白2（IGF2BP2）的转录激活，从而增强CBP耐药性和肿瘤生长。值得注意的是，该功能独立于PRMT1的酶活性，这使其与在精氨酸甲基化中已确立的作用有所不同。此外，前B细胞白血病同源盒2（PBX2）被确定为一种上游转录激活因子，它结合PRMT1启动子，驱动其过表达并加强这一致癌网络。在临床上，高PBX2、PRMT1、SMARCC1和IGF2BP2表达与HNSCC患者的恶性进展和不良预后相关。这项研究揭示了PRMT1以前未被认识的非催化功能，并突出了PBX2-PRMT1-SWI/SNF-IGF2BPZ轴作为克服HNSCC中CBP耐药性的潜在治疗靶点。
