Dominant-negative HIF-3 alpha 4 suppresses VHL-null renal cell carcinoma progression.
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-alpha due to a failure of VHL as a substrate-recognition component of an E3 ubiquitin ligase complex to target HIFalpha for oxygen-dependent ubiquitin-mediated destruction. Stabilization of HIF-2alpha, but not HIF-1alpha, is the critical oncogenic event upon the functional loss of VHL in the development of CC-RCC. Here, we show that HIF-3alpha4, an alternatively spliced variant of human HIF-3alpha with similar domain structure as the murine inhibitory PAS protein (IPAS), forms an abortive transcriptional complex with HIF-2alpha and 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-3alpha4 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-3alpha4 is a naturally occurring dominant-negative HIF-3alpha splice isoform with tumor suppressive activity and support the targeted delivery of HIF-3alpha4 as a potential therapeutic option to curtail HIF-dependent tumor progression.
Maynard
Mindy A
MA
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Evans
Andrew J
AJ
Shi
Wei
W
Kim
William Y
WY
Liu
Fei-Fei
FF
Ohh
Michael
M
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D045744:Cell Line, Tumor; D018450:Disease Progression; D005799:Genes, Dominant / Q000502:physiology; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D012097:Repressor Proteins; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000037:antagonists & inhibitors* / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C116973:HIF3A protein, human