Transcriptional regulation of hypoxia-inducible factor 1alpha by HIPK2 suggests a novel mechanism to restrain tumor growth.
Article Details
- CitationCopy to clipboard
Nardinocchi L, Puca R, Guidolin D, Belloni AS, Bossi G, Michiels C, Sacchi A, Onisto M, D'Orazi G
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.
- PubMed ID
- 19046997 [ View in PubMed]
- 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.