Ando Toshinori, Okamoto Kento, Ueda Yume, Kataoka Nanako, Shintani Tomoaki, Yanamoto Souichi, Miyauchi Mutsumi, Kajiya Mikihito
Center of Oral Clinical Examination, Hiroshima University Hospital, Hiroshima, 734-8551, Japan.
Department of Oral Oncology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8553, Japan.
Oncogenesis. 2024 Jul 15;13(1):25. doi: 10.1038/s41389-024-00527-0.
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.
河马通路及其下游效应分子Yes相关蛋白/含PDZ结合基序的转录共激活因子（YAP/TAZ）对细胞生长和器官发育至关重要。新出现的证据表明，在包括头颈部鳞状细胞癌（HNSCC）在内的实体癌中，河马通路和YAP/TAZ经常因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）增强几种转录因子的转录活性，还调节mRNA剪接。降解RBM39的茚地那韦诱导可变剪接，导致细胞死亡。然而，茚地那韦的临床试验未能显示出有效性。因此，迫切需要阐明对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确定RBM39是一种新型的YAP/TAZ相互作用分子。RBM39促进YAP/TAZ转录活性。我们进一步阐明，茚地那韦降低RBM39/YAP/TAZ介导的整合素或胶原蛋白表达，从而使对细胞存活重要的粘着斑激酶（FAK）失活。此外，茚地那韦还诱导细胞周期或DNA代谢相关基因的可变剪接。YAP/TAZ的过度激活延迟了茚地那韦诱导的RBM39降解，这恢复了整合素/胶原蛋白表达以激活FAK和可变剪接，从而在体外和体内赋予对茚地那韦的抗性。我们的发现可能有助于开发一种针对YAP/TAZ/RBM39相互作用的新型癌症疗法。
