Résumé
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.
langue originale | Anglais |
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Pages (de - à) | 368-377 |
Nombre de pages | 10 |
journal | Biochimica et Biophysica Acta - Molecular Cell Research |
Volume | 1793 |
Numéro de publication | 2 |
Les DOIs | |
Etat de la publication | Publié - févr. 2009 |