Alternative pre-mRNA splicing (AS) is a biological process that results in proteomic diversity. However, implications of AS alterations in cancer remain poorly understood. Herein, we performed a comprehensive AS analysis in cancer driver gene transcripts across fifteen cancer types and found global alterations in inclusion rates of the PBAF SWI/SNF chromatin remodeling complex subunit Polybromo 1 (PBRM1) exon 27 (E27) in most types of cancer tissues compared with those in normal tissues. Further analysis confirmed that PBRM1 E27 is excluded by the direct binding of RBFOX2 to intronic UGCAUG elements. In addition, the E27-included PBRM1 isoform upregulated PD-L1 expression via enhanced PBAF complex recruitment to the PD-L1 promoter. PBRM1 wild-type patients with clear cell renal cell carcinoma were resistant to PD-1 blockade therapy when they expressed low RBFOX2 mRNA levels. Overall, our study suggests targeting of RBFOX2-mediated AS of PBRM1 as a potential therapeutic strategy for immune checkpoint blockade.

中文翻译：

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PBRM1 的选择性剪接介导肾癌对 PD-1 阻断治疗的耐药性。


选择性前体 mRNA 剪接 （AS） 是一种导致蛋白质组学多样性的生物过程。然而，AS 改变对癌症的影响仍然知之甚少。在此，我们对 15 种癌症类型的癌症驱动基因转录本进行了全面的 AS 分析，发现与正常组织相比，大多数类型癌症组织中 PBAF SWI/SNF 染色质重塑复合物亚基多溴 1 （PBRM1） 外显子 27 （E27） 的包含率发生了整体变化。进一步分析证实，RBFOX2 与内含含子 UGCAUG 元件的直接结合排除了 PBRM1 E27。此外，E27 包含的 PBRM1 亚型通过增强 PBAF 复合物募集到 PD-L1 启动子，上调 PD-L1 表达。PBRM1 野生型透明细胞肾细胞癌患者在表达低 RBFOX2 mRNA 水平时对 PD-1 阻断治疗耐药。总体而言，我们的研究表明靶向 RBFOX2 介导的 PBRM1 AS 作为免疫检查点阻断的潜在治疗策略。