SRY-Box transcription factor 9 triggers YAP nuclear entry via direct interaction in tumors

• Published in: Signal transduction and targeted therapy 2024-04, Vol.9 (1), p.96-96, Article 96
• Main Authors: Qian, Hui, Ding, Chen-Hong, Liu, Fang, Chen, Shi-Jie, Huang, Chen-Kai, Xiao, Meng-Chao, Hong, Xia-Lu, Wang, Ming-Chen, Yan, Fang-Zhi, Ding, Kai, Cui, Ya-Lu, Zheng, Bai-Nan, Ding, Jin, Luo, Cheng, Zhang, Xin, Xie, Wei-Fen
• Format: Article
• Language: English
• Subjects: 631/67/1059/153; 631/67/395; Active Transport, Cell Nucleus - genetics; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Cancer; Cancer Research; Cell Biology; Cell growth; Cell Line, Tumor; Cell Nucleus - genetics; Cell Nucleus - metabolism; Cytoplasm; Gastroenterology; Hospitals; Humans; Internal Medicine; Localization; Medical prognosis; Medicine; Medicine & Public Health; Methylation; Mice; Molecular modelling; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Nuclear transport; Oncology; Pathology; Peptides; Protein-Arginine N-Methyltransferases - genetics; Protein-Arginine N-Methyltransferases - metabolism; Proteins; Repressor Proteins - genetics; Repressor Proteins - metabolism; Signal transduction; Sox9 protein; SOX9 Transcription Factor - genetics; SOX9 Transcription Factor - metabolism; Stem cells; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Tumors; YAP-Signaling Proteins - genetics; YAP-Signaling Proteins - metabolism; Yes-associated protein
• ISSN: 2059-3635; 2095-9907; 2059-3635
• DOI: 10.1038/s41392-024-01805-4

The translocation of YAP from the cytoplasm to the nucleus is critical for its activation and plays a key role in tumor progression. However, the precise molecular mechanisms governing the nuclear import of YAP are not fully understood. In this study, we have uncovered a crucial role of SOX9 in the activation of YAP. SOX9 promotes the nuclear translocation of YAP by direct interaction. Importantly, we have identified that the binding between Asp-125 of SOX9 and Arg-124 of YAP is essential for SOX9-YAP interaction and subsequent nuclear entry of YAP. Additionally, we have discovered a novel asymmetrical dimethylation of YAP at Arg-124 (YAP-R124me2a) catalyzed by PRMT1. YAP-R124me2a enhances the interaction between YAP and SOX9 and is associated with poor prognosis in multiple cancers. Furthermore, we disrupted the interaction between SOX9 and YAP using a competitive peptide, S-A1, which mimics an α-helix of SOX9 containing Asp-125. S-A1 significantly inhibits YAP nuclear translocation and effectively suppresses tumor growth. This study provides the first evidence of SOX9 as a pivotal regulator driving YAP nuclear translocation and presents a potential therapeutic strategy for YAP-driven human cancers by targeting SOX9-YAP interaction.