USP9X destabilizes pVHL and promotes cell proliferation

// Cong Zhang 1, * , Zuohan Peng 1, * , Minglu Zhu 1 , Penglong Wang 1 , Xiao Du 1 , Xiang Li 1 , Yu Liu 1 , Yan Jin 1 , Michael A. McNutt 1 , Yuxin Yin 1 1 Institute of Systems Biomedicine, State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Tumor Systems Biology, Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Peking-Tsinghua Center for Life Sciences, Beijing, 100191, China * These authors have contributed equally to this work Correspondence to: Yuxin Yin, email: yinyuxin@hsc.pku.edu.cn Keywords: USP9X, pVHL, mutation, protein stability, proliferation Received: January 06, 2016     Accepted: July 26, 2016     Published: August 09, 2016 ABSTRACT Numerous mutations of the Von Hippel-Lindau ( VHL ) gene have been reported to cause dysfunction of VHL protein (pVHL) and lead to processes related to tumor progression. pVHL acts as an E3 ligase and degrades downstream targets, such as hypoxia-inducible transcription factor (HIF) which is essential for tumor growth. Previous studies reported reduction of VHL protein, rather than mRNA in VHL-related tumor patients, suggesting that instability of the pVHL protein itself is a primary cause of dysfunction. Regulation of pVHL stability has therefore been a major focus of research. We report that ubiquitin-specific protease 9X (USP9X), which is a deubiquitinase binds and promotes degradation of both wild-type and mutants of pVHL that retain E3 ligase function, thus activating the HIF pathway. USP9X degrades pVHL through protection of its substrate, the newly identified pVHL E3 ligase Smurf1. In addition, USP9X activates glycolysis and promotes cell proliferation through pVHL. Treatment with a USP9X inhibitor shows an effect similar to USP9X knockdown in pVHL induction, and suppresses HIF activity. Our findings demonstrate that USP9X is a novel regulator of pVHL stability, and USP9X may be a therapeutic target for treatment of VHL-related tumors.