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

Lavinia Nardinocchi, Rosa Puca, Diego Guidolin, Anna S. Belloni, Gianluca Bossi, Carine Michiels, Ada Sacchi, Maurizio Onisto, Gabriella D'Orazi

Research output: Contribution to journalArticle

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-1α mRNA and of its target VEGF in tumor cells, we evaluated the role of HIPK2 in transcriptional regulation of HIF-1α. We found that HIPK2 overexpression downmodulated both HIF-1α reporter activity and mRNA levels and showed that HIPK2 was bound in vivo to the HIF-1α promoter likely in a multiprotein co-repressor complex with histone deacetylase 1 (HDAC1). Thus, the HIF-1α promoter was strongly acetylated following HIPK2 knockdown. The HIF-1α-dependent VEGF transcription was evaluated by co-transfection of a dominant negative (DN) construct of HIF-1α that inhibited VEGF reporter activity induced by HIPK2 knockdown. HIF-1α 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-1α that might play a critical role in VEGF expression.

Original languageEnglish
Pages (from-to)368-377
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1793
Issue number2
DOIs
Publication statusPublished - Feb 2009

Keywords

  • ChIP
  • HIF-1α mRNA
  • HIF-1α promoter
  • HIPK2
  • Luciferase activity
  • RNA interference

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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