YAP/TAZ与RBM39相互作用赋予Indisulam抗药性

YAP/TAZ interacts with RBM39 to confer resistance against indisulam

Oncogenesis

影响因子:6.4

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

DOI: 10.1038/s41389-024-00527-0

摘要

Hippo通路及其下游效应因子YAP/TAZ在细胞生长和器官发育中起关键作用。新兴证据显示，Hippo通路和YAP/TAZ在多种实体瘤中频繁因多种遗传变异而失调，包括头颈部鳞状细胞癌（HNSCC）；然而，YAP/TAZ-核内相互作用组的具体情况仍不清楚。RNA结合基序蛋白RBM39增强多种转录因子的转录活性，还调控mRNA剪接。Indisulam通过降解RBM39诱导可变剪接，导致细胞死亡，但临床试验显示其疗效有限。因此，阐明抗剪接抑制剂的耐药机制尤为紧迫。本研究通过蛋白质组分析，首次鉴定RBM39为YAP/TAZ的相互作用蛋白。RBM39促进YAP/TAZ的转录活性。我们进一步发现，Indisulam降低了RBM39/YAP/TAZ介导的整合素或胶原蛋白表达，从而使细胞存活所必需的焦点粘附激酶（FAK）失活。此外，Indisulam还诱导与细胞周期或DNA代谢相关基因的可变剪接。YAP/TAZ的过度激活延缓了Indisulam诱导的RBM39降解，恢复了整合素/胶原表达，激活了FAK，并引起可变剪接，从而在体内外赋予细胞对Indisulam的抗药性。我们的研究结果有助于开发聚焦于YAP/TAZ/RBM39相互作用的创新癌症治疗策略。

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.