Hippo 通路及其下游效应子，即具有 PDZ 结合基序的 Yes 相关蛋白/转录共激活子 (YAP/TAZ)，对于细胞生长和器官发育至关重要。新出现的证据表明，Hippo 通路和 YAP/TAZ 经常因实体癌（包括头颈鳞状细胞癌 (HNSCC)）中的多种基因改变而失调；然而，YAP/TAZ-核相互作用组仍不清楚。 RNA 结合基序蛋白 39 (RBM39) 增强多种转录因子的转录活性，并调节 mRNA 剪接。 Indisulam 降解 RBM39 诱导选择性剪接，导致细胞死亡。然而，indisulam 的临床试验未能显示其有效性。因此，迫切需要阐明剪接抑制剂的耐药机制。在本研究中，我们通过蛋白质组分析将 RBM39 鉴定为一种新型 YAP/TAZ 相互作用分子。 RBM39 促进 YAP/TAZ 转录活性。我们进一步阐明，indisulam 减少 RBM39/YAP/TAZ 介导的整合素或胶原表达，从而使对细胞存活重要的粘着斑激酶 (FAK) 失活。此外，indisulam 还诱导细胞周期或 DNA 代谢相关基因的选择性剪接。 YAP/TAZ 过度激活延迟了 indisulam 诱导的 RBM39 降解，从而恢复了整合素/胶原表达以激活 FAK 和选择性剪接，从而在体外和体内赋予对 indisulam 的抗性。我们的研究结果可能有助于开发一种关注 YAP/TAZ/RBM39 相互作用的新型癌症疗法。© 2024。作者。

The Hippo pathway and its downstream effectors, Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ), are essential for cell growth and organ development. Emerging evidence revealed that the Hippo pathway and YAP/TAZ are frequently dysregulated by multiple genetic alterations in solid cancers including head and neck squamous cell carcinoma (HNSCC); however, the YAP/TAZ-nuclear interactome remains unclear. RNA-binding motif protein 39 (RBM39) enhances transcriptional activity of several transcription factors and also regulates mRNA splicing. Indisulam degrading RBM39 induces alternative splicing, leading to cell death. However, clinical trials of indisulam have failed to show effectiveness. Therefore, clarifying the resistance mechanism against splicing inhibitors is urgently required. In this study, we identified RBM39 as a novel YAP/TAZ-interacting molecule by proteome analysis. RBM39 promoted YAP/TAZ transcriptional activity. We further elucidated that indisulam reduces RBM39/YAP/TAZ-mediated integrin or collagen expression, thereby inactivating focal adhesion kinase (FAK) important for cell survival. Moreover, indisulam also induced alternative splicing of cell cycle- or DNA metabolism-related genes. YAP/TAZ hyperactivation delayed indisulam-induced RBM39 degradation, which restored the integrin/collagen expression to activate FAK, and alternative splicing, thereby conferring resistance against indisulam in vitro and in vivo. Our findings may aid to develop a novel cancer therapy focusing on YAP/TAZ/RBM39 interaction.© 2024. The Author(s).