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

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-1 alpha mRNA and of its target VEGF in tumor cells, we evaluated the role of HIPK2 in transcriptional regulation of HIF-1 alpha. We found that HIPK2 overexpression downmodulated both HIF-1 alpha reporter activity and mRNA levels and showed that HIPK2 was bound in vivo to the HIF-1 alpha promoter likely in a multiprotein co-repressor complex with histone deacetylase 1 (HDAC1). Thus, the HIF-1 alpha promoter was strongly acetylated following HIPK2 knockdown. The HIF-Independent VEGF transcription was evaluated by co-transfection of a dominant negative (DN) construct of HIF-1 alpha that inhibited VEGF reporter activity induced by HIPK2 knockdown. HIF-1 alpha 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-1 alpha that might play a critical role in VEGF expression. (c) 2008 Elsevier B.V. All rights reserved.