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.
Highlights
PVHL is an E3 ligase containing α and β domains which is ubiquitously expressed in most normal tissues and cell types [1,2,3]
Our study reveals novel mechanistic information regarding regulation of pVHL stability, and shows that an associated protein ubiquitin-specific protease 9X (USP9X) participates in the degradation process of pVHL and pVHL mutants through a newly identified pVHL E3 ligase Smurf1
We show that one USP9X inhibitor is highly effective in induction of both wild type and mutant pVHL
Summary
PVHL is an E3 ligase containing α and β domains which is ubiquitously expressed in most normal tissues and cell types [1,2,3]. PVHL recognizes hydroxylated HIFα and targets it for degradation [9,10,11,12]. When cells respond to hypoxic conditions, lack of hydroxylation allows HIFα to escape pVHL-dependent degradation and activate transcription of genes involved in anaerobic metabolism, cell growth and angiogenesis [13,14,15,16]. In addition to HIFα, pVHL targets a number of proteins involved in DNA damage repair, cell cycle regulation, autophagy, assembly of extracellular matrix and anaerobic metabolism for degradation [18,19,20,21,22,23,24,25,26]. In addition to HIFα, pVHL targets a number of proteins involved in DNA damage repair, cell cycle regulation, autophagy, assembly of extracellular matrix and anaerobic metabolism for degradation [18,19,20,21,22,23,24,25,26]. pVHL modulates NF-κB activity through HIFα-dependent or -independent pathways to influence apoptosis [27,28,29,30]
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