Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
Oncogene. 2018 May;37(18):2422-2431. doi: 10.1038/s41388-018-0134-2. Epub 2018 Feb 16.
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.
Yes 相关蛋白 1（YAP1）是 Hippo 通路的主要下游效应因子，作为转录调节剂发挥作用，在细胞控制器官大小和肿瘤生长方面具有重要作用。在不同类型的人类癌症中，YAP1 的致癌活性升高，这有助于癌细胞的存活和化疗耐药性。然而，YAP1 在癌症中过表达的分子机制尚不清楚。在这里，我们证明去泛素化酶 USP9X 去泛素化并稳定 YAP1，从而促进癌细胞的存活。在人乳腺癌细胞系和患者样本中，USP9X 表达增加与 YAP1 蛋白增加相关。此外，USP9X 的耗竭会增加 YAP1 的多泛素化，进而增加 YAP1 的周转率和细胞对化疗的敏感性。总的来说，我们的研究确立了 USP9X-YAP1 轴作为乳腺癌的重要调节机制，并为治疗乳腺癌的潜在治疗干预提供了依据。
