Transcriptional regulation of hypoxia-inducible factor 1alpha by HIPK2 suggests a novel mechanism to restrain tumor growth

Biochim Biophys Acta. 2009 Feb;1793(2):368-77. doi: 10.1016/j.bbamcr.2008.10.013. Epub 2008 Nov 6.

Abstract

HIPK2 has been implicated in restraining tumor progression by more than one mechanism, involving both its catalytic and transcriptional co-repressor functions. Starting from the finding that HIPK2 knockdown by RNA-interference (HIPK2i) induced significant up-regulation of HIF-1alpha mRNA and of its target VEGF in tumor cells, we evaluated the role of HIPK2 in transcriptional regulation of HIF-1alpha. We found that HIPK2 overexpression downmodulated both HIF-1alpha reporter activity and mRNA levels and showed that HIPK2 was bound in vivo to the HIF-1alpha promoter likely in a multiprotein co-repressor complex with histone deacetylase 1 (HDAC1). Thus, the HIF-1alpha promoter was strongly acetylated following HIPK2 knockdown. The HIF-1alpha-dependent VEGF transcription was evaluated by co-transfection of a dominant negative (DN) construct of HIF-1alpha that inhibited VEGF reporter activity induced by HIPK2 knockdown. HIF-1alpha and VEGF up-regulation in HIPK2i cells correlated with increased vascularity of tumor xenografts in vivo and tube formation in HUVEC in vitro. These findings provide the first evidence of HIPK2-mediated transcriptional regulation of HIF-1alpha that might play a critical role in VEGF expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation
  • Chromatin Assembly and Disassembly / genetics
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Mice
  • Neoplasms / blood supply
  • Neoplasms / enzymology
  • Neoplasms / genetics*
  • Neoplasms / pathology*
  • Neovascularization, Pathologic / genetics
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / metabolism*
  • Repressor Proteins / metabolism
  • Transcription, Genetic*
  • Vascular Endothelial Growth Factor A / genetics

Substances

  • Carrier Proteins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Repressor Proteins
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • HIPK2 protein, human
  • Protein-Serine-Threonine Kinases