Zhang Tongjia, Wang Shujie, Zhou Yue, Jiao Zitao, Lu Kejia, Liu Xinyi, Li Hui, Jiang Wei, Zhang Xiaowei
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science Center, Beijing, China.
PLoS Biol. 2025 Jun 4;23(6):e3002846. doi: 10.1371/journal.pbio.3002846. eCollection 2025 Jun.
Indisulam, a sulfonamide-based compound, is employed as a second-line therapy for NSCLC due to its anti-tumor activity. However, its clinical efficacy is hindered by acquired resistance, the molecular basis of which remains poorly understood. Here, we demonstrate that hypermethylation of RNA-binding protein 39 (RBM39), a specific target of Indisulam, is closely associated with Indisulam resistance. PRMT6 methylates RBM39 at R92. This methylation inhibits Indisulam-induced ubiquitination and proteasomal degradation of RBM39, increases RBM39 protein levels, promotes alternative splicing and expression of proto-oncogenes, and ultimately leads to malignant proliferation and metastasis of NSCLC cells and tumor growth in xenograft mouse models. Inhibiting PRMT6 with MS023 or mutating the RBM39 methylation site enhances Indisulam sensitivity in NSCLC and significantly improves its anti-tumor efficacy. Our findings identify methylated RBM39 as a key biomarker of Indisulam resistance and suggest a potential therapeutic strategy for NSCLC.
因具有抗肿瘤活性，基于磺酰胺的化合物茚地那韦被用作非小细胞肺癌（NSCLC）的二线治疗药物。然而，其临床疗效受到获得性耐药的阻碍，而获得性耐药的分子基础仍知之甚少。在此，我们证明了茚地那韦的特异性靶点——RNA结合蛋白39（RBM39）的高甲基化与茚地那韦耐药密切相关。蛋白精氨酸甲基转移酶6（PRMT6）使RBM39的第92位精氨酸发生甲基化。这种甲基化抑制了茚地那韦诱导的RBM39泛素化和蛋白酶体降解，增加了RBM39蛋白水平，促进了原癌基因的可变剪接和表达，并最终导致NSCLC细胞的恶性增殖和转移以及异种移植小鼠模型中的肿瘤生长。用MS023抑制PRMT6或突变RBM39甲基化位点可增强NSCLC对茚地那韦的敏感性，并显著提高其抗肿瘤疗效。我们的研究结果确定甲基化的RBM39为茚地那韦耐药的关键生物标志物，并为NSCLC提出了一种潜在的治疗策略。
