The Yes-associated protein 1 (YAP1), a major downstream effector of the Hippo pathway, functions as a transcriptional regulator and has an important role in cellular control of organ size and tumor growth. Elevated oncogenic activity of YAP1 has been clarified in different types of human cancers, which contributes to cancer cell survival and chemoresistance. However, the molecular mechanism of YAP1 overexpression in cancer is still not clear. Here we demonstrate that the deubiquitination enzyme USP9X deubiquitinates and stabilizes YAP1, thereby promoting cancer cell survival. Increased USP9X expression correlates with increased YAP1 protein in human breast cancer cell lines and patient samples. Moreover, depletion of USP9X increases YAP1 polyubiquitination, which in turn elevates YAP1 turnover and cell sensitivity to chemotherapy. Overall, our study establishes the USP9X-YAP1 axis as an important regulatory mechanism of breast cancer and provides a rationale for potential therapeutic interventions in the treatment of breast cancer.

中文翻译：

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去泛素酶 USP9X 促进肿瘤细胞存活，并通过稳定 YAP1 赋予化疗耐药性。


Yes 相关蛋白 1 (YAP1) 是 Hippo 通路的主要下游效应子，作为转录调节因子发挥作用，在器官大小和肿瘤生长的细胞控制中发挥重要作用。在不同类型的人类癌症中，YAP1 的致癌活性升高已被阐明，这有助于癌细胞的存活和化疗耐药性。然而，YAP1在癌症中过度表达的分子机制仍不清楚。在这里，我们证明去泛素化酶 USP9X 去泛素化并稳定 YAP1，从而促进癌细胞存活。 USP9X 表达增加与人乳腺癌细胞系和患者样本中 YAP1 蛋白增加相关。此外，USP9X 的消耗会增加 YAP1 多聚泛素化，从而提高 YAP1 周转率和细胞对化疗的敏感性。总体而言，我们的研究将 USP9X-YAP1 轴确立为乳腺癌的重要调节机制，并为乳腺癌治疗中的潜在治疗干预措施提供了理论依据。