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

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

Author information

  • 1Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, (00158) Rome, Italy.

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.

PMID:
19046997
[PubMed - indexed for MEDLINE]
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