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.

YAP 从细胞质易位到细胞核对其激活至关重要，并在肿瘤进展中发挥关键作用。然而，控制 YAP 核输入的精确分子机制尚不完全清楚。在这项研究中，我们发现了 SOX9 在 YAP 激活中的关键作用。 SOX9 通过直接相互作用促进 YAP 的核转位。重要的是，我们已经确定 SOX9 的 Asp-125 和 YAP 的 Arg-124 之间的结合对于 SOX9-YAP 相互作用和随后 YAP 进入核至关重要。此外，我们还发现了 PRMT1 催化的 YAP Arg-124 (YAP-R124me2a) 的新型不对称二甲基化。 YAP-R124me2a 增强 YAP 和 SOX9 之间的相互作用，并与多种癌症的不良预后相关。此外，我们使用竞争性肽 S-A1 破坏了 SOX9 和 YAP 之间的相互作用，S-A1 模拟了含有 Asp-125 的 SOX9 的 α 螺旋。 S-A1显着抑制YAP核转位，有效抑制肿瘤生长。这项研究提供了 SOX9 作为驱动 YAP 核易位的关键调节因子的第一个证据，并通过靶向 SOX9-YAP 相互作用为 YAP 驱动的人类癌症提供了潜在的治疗策略。