TY - JOUR
T1 - The deubiquitinase USP9X promotes tumor cell survival and confers chemoresistance through YAP1 stabilization
AU - Li, Lei
AU - Liu, Tongzheng
AU - Li, Yunhui
AU - Wu, Chenming
AU - Luo, Kuntian
AU - Yin, Yujiao
AU - Chen, Yuping
AU - Nowsheen, Somaira
AU - Wu, Jinhuan
AU - Lou, Zhenkun
AU - Yuan, Jian
N1 - Funding Information:
Acknowledgements We thank Drs William G. Kaelin, Qing Zhang, Kunliang Guan, and Junjie Chen for kindly providing constructs. This study was supported by NSFC (81773758, 81572770, and 31371367), National Institutes of Health grant (CA203971, CA203561, CA189666, and CA130996), Ovarian Cancer SPORE in Mayo Clinic (P50CA136393), and the Pilot Project Award Program of Mayo Clinic Fraternal Order of Eagles Cancer Research Fund.
Publisher Copyright:
© 2018 Macmillan Publishers Limited, part of Springer Nature.
PY - 2018/5/1
Y1 - 2018/5/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41388-018-0134-2
DO - 10.1038/s41388-018-0134-2
M3 - Article
C2 - 29449692
AN - SCOPUS:85042066627
SN - 0950-9232
VL - 37
SP - 2422
EP - 2431
JO - Oncogene
JF - Oncogene
IS - 18
ER -