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Dominant-Negative HIF-3α4 Suppresses VHL-Null Renal Cell Carcinoma Progression

Mindy A. Maynard, Andrew J. Evans, Wei Shi, William Y. Kim, Fei-Fei Liu and Michael Ohh

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The most prevalent mutations associated with the development of clear-cell renal cell carcinoma (CC-RCC) are the loss-of-function mutations of von Hippel-Lindau (VHL) tumor suppressor gene. These mutations invariably result in an inappropriate accumulation of HIF-α due to a failure of VHL as a substrate-recognition component of an E3 ubiquitin ligase complex to target HIFα for oxygen-dependent ubiquitin-mediated destruction. Stabilization of HIF-2α, but not HIF-1α, is the critical oncogenic event upon the functional loss of VHL in the development of CC-RCC. Here, we show that HIF-3α4, an alternatively spliced variant of human HIF-3α with similar domain structure as the murine inhibitory PAS protein (IPAS), forms an abortive transcriptional complex with HIF-2α, prevents the engagement of HIF-2 to the hypoxia-responsive elements (HREs) located in the promoter/enhancer regions of hypoxia-inducible genes. In addition, the re-expression of HIF-3α4 in VHL-null 786-O CC-RCC cells via adenovirus decreases the endogenous expression of HIF-2-driven gene expression and suppresses the growth of 786-O tumor xenografts in SCID mice. These results suggest that HIF-3α4 is a naturally occurring dominant-negative HIF-3α splice isoform with tumor suppressive activity and support the targeted delivery of HIF-3α4 as a potential therapeutic option to curtail HIF-dependent tumor progression.

Authors

Mindy A. Maynard

University of Toronto; Toronto, Ontario Canada

Andrew J. Evans

University of Toronto; Toronto, Ontario Canada

Wei Shi

University Health Network; Toronto, Ontario Canada

William Y. Kim

University of North Carolina at Chapel Hill; Chapel Hill, NC

Fei-Fei Liu

University Health Network; Toronto, Ontario Canada

Michael Ohh

University of Toronto; Toronto, Ontario Canada

Purchase article for $19

Subscribe to this journal for $129/year