YAP/TAZ与RBM39相互作用，以赋予对Indisulam的抗性
YAP/TAZ interacts with RBM39 to confer resistance against indisulam
影响因子:6.40000
分区:医学2区 / 肿瘤学2区
发表日期:2024 Jul 15
作者:
Toshinori Ando, Kento Okamoto, Yume Ueda, Nanako Kataoka, Tomoaki Shintani, Souichi Yanamoto, Mutsumi Miyauchi, Mikihito Kajiya
摘要
HIPPO途径及其下游效应子，与PDZ结合基序（YAP/TAZ）相关的蛋白质/转录共激活因子（YAP/TAZ）对于细胞生长和器官发育至关重要。新兴的证据表明，河马途径和YAP/TAZ经常因固体癌症（包括头颈鳞状细胞癌（HNSCC））的多种遗传改变而失调。但是，YAP/TAZ核相互作用组仍不清楚。 RNA结合基序蛋白39（RBM39）增强了几种转录因子的转录活性，并调节mRNA剪接。 Indisulam降解RBM39诱导替代剪接，导致细胞死亡。但是，Indisulam的临床试验未能显示出有效性。因此，迫切需要澄清防止剪接抑制剂的电阻机制。在这项研究中，我们通过蛋白质组分析将RBM39鉴定为一种新型的YAP/TAZ相互作用分子。 RBM39促进了YAP/TAZ转录活性。我们进一步阐明了indisulam降低了RBM39/YAP/TAZ介导的整联蛋白或胶原蛋白的表达，从而使局灶性粘附激酶（FAK）灭活对细胞存活很重要。此外，Indisulam还诱导了与细胞周期或DNA代谢相关基因的替代剪接。 YAP/TAZ过度激活延迟了Indisulam诱导的RBM39降解，从而恢复了整联蛋白/胶原蛋白表达以激活FAK和替代剪接，从而在体外和体内赋予了对Indisulam的抗性。我们的发现可能有助于开发针对YAP/TAZ/RBM39相互作用的新型癌症疗法。
Abstract
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.