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. © 2008 Elsevier B.V. All rights reserved.
Original language | English |
---|---|
Pages (from-to) | 368-377 |
Number of pages | 10 |
Journal | Biochimica et Biophysica Acta - Molecular Cell Research |
Volume | 1793 |
Issue number | 2 |
DOIs | |
Publication status | Published - Feb 2009 |
Keywords
- ChIP
- HIF-1α mRNA
- HIF-1α promoter
- HIPK2
- Luciferase activity
- RNA interference