Abstract
The hypoxic microenvironment contributes to embryonic development and tumor progression through stabilization of the potent transcriptional factor HIFα. In normoxia, the tumor suppressor protein VHL acts as an E3 ubiquitin ligase to target HIFα for proteolytic destruction. Increasing evidence shows that VHL is a multifunctional adaptor involved in inhibition of HIFα-dependent and independent cellular processes. However, the molecular effect of hypoxic stress on VHL functions remains elusive. Here we report that PIASy, a SUMO E3 ligase upregulated in hypoxia, interacts with VHL and induces VHL SUMOylation on lysine residue 171. Moreover, PIASy-mediated SUMO1 modification induces VHL oligomerization and abrogates its inhibitory function on tumor cell growth, migration and clonogenicity. Knockdown of PIASy by small interfering RNA leads to reduction of VHL oligomerization and increases HIF1α degradation. These findings reveal a unique molecular strategy for inactivation of VHL under hypoxic stress.
Highlights
The ability of cells to recognize and respond to a low-oxygen environment is critical in many physiological and pathological conditions [1,2]
The ability of von Hippel Lindau (VHL) to target HIFa for proteolysis as a ubiquitin E3 ligase is one of its major function [5], increasing evidence have demonstrated that VHL is a multipurpose adaptor for involvement in the inhibition of angiogenesis, cell cycle exit and fibronectin matrix assembly in a HIF-dependent or independent manner [30,31,32]
A great deal of effort has been put into studying the molecular mechanism of hypoxia stress on HIFa stabilization via posttranslational regulation [8,23,34,35,36], it still remains unclear whether hypoxia affects overall VHL tumor suppressor function
Summary
The ability of cells to recognize and respond to a low-oxygen environment (hypoxia) is critical in many physiological and pathological conditions [1,2]. The transcriptional factor HIF (hypoxia-inducible factor) is a central regulator of this pathway. When cells are exposed to a hypoxic environment, this hydroxylation-mediated degradation pathway is blocked, thereby allowing HIF1a to accumulate in the nucleus, where it binds to the constitutively expressed HIF1b and transactivates hypoxia-responsive genes that are implicated in cellular metabolism, angiogenesis, invasion, and metastasis [3,7]. Other studies suggest that VHL is able to target HIF1a for destruction in an hydroxylation independent manner during hypoxia [8]. These studies indicated that VHL is a critical regulator of the ubiquitous oxygen-sensing pathway
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