Dominant-negative HIF-3 alpha 4 suppresses VHL-null renal cell carcinoma progression

Cell Cycle. 2007 Nov 15;6(22):2810-6. doi: 10.4161/cc.6.22.4947. Epub 2007 Aug 29.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / pathology*
  • Carcinoma, Renal Cell / prevention & control*
  • Cell Line, Tumor
  • Disease Progression
  • Genes, Dominant / physiology
  • Humans
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology*
  • Kidney Neoplasms / prevention & control*
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • Transcription Factors / biosynthesis*
  • Transcription Factors / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / antagonists & inhibitors*
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics*
  • Xenograft Model Antitumor Assays / methods

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • HIF3A protein, human
  • Transcription Factors
  • Von Hippel-Lindau Tumor Suppressor Protein