The deubiquitinase USP9X promotes tumor cell survival and confers chemoresistance through YAP1 stabilization

The Yes-associated protein 1 (YAP1), a major downstream effector of the Hippo pathway, functions as a transcriptional regulator and plays 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 cancers 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 lines and patient samples. Moreover, depletion of USP9X increases YAP1 poly-ubiquitination, 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.