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USP9X destabilizes pVHL and promotes cell proliferation
Cong Zhang1, Zuohan Peng1, Minglu Zhu1
1Institute 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.
Ubiquitin-specific protease 9X (USP9X) degrades Von Hippel-Lindau protein (pVHL), a key factor in tumor growth. Inhibiting USP9X stabilizes pVHL, suppressing tumor-promoting pathways.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Von Hippel-Lindau (VHL) gene mutations cause VHL protein (pVHL) dysfunction, promoting tumor progression.
- pVHL, an E3 ligase, degrades hypoxia-inducible transcription factor (HIF), crucial for tumor growth.
- pVHL protein instability, not mRNA reduction, is linked to VHL-related tumors, highlighting the need to study pVHL stability.
Purpose of the Study:
- To investigate the role of ubiquitin-specific protease 9X (USP9X) in regulating pVHL stability.
- To elucidate the mechanism by which USP9X affects pVHL function and downstream pathways.
- To assess the therapeutic potential of targeting USP9X in VHL-related tumors.
Main Methods:
- Investigated the interaction between USP9X and pVHL (wild-type and mutants).
- Assessed the impact of USP9X on pVHL degradation and HIF pathway activation.
- Examined the effect of USP9X inhibition on pVHL levels, HIF activity, glycolysis, and cell proliferation.
Main Results:
- USP9X binds to and promotes the degradation of both wild-type and mutant pVHL.
- USP9X degrades pVHL by protecting its substrate, Smurf1, a newly identified pVHL E3 ligase.
- USP9X activation of glycolysis and cell proliferation is mediated through pVHL.
- USP9X inhibition or knockdown stabilizes pVHL, suppresses HIF activity, and inhibits tumor cell proliferation.
Conclusions:
- USP9X is a novel regulator of pVHL stability, promoting its degradation.
- USP9X plays a significant role in activating the HIF pathway and promoting tumor growth.
- USP9X inhibition represents a potential therapeutic strategy for VHL-related tumors.
