Abstract 2048: USF2 is HIF2α specific co-transcriptional activator

Abstract

Abstract Hypoxia inducible factor HIF1α, and in particular HIF2α have been shown to drive malignant progression by activation of angiogenesis, proliferation, anaerobic metabolism, and other processes that enable tumor cells to survive or to escape their O2-deficient microenvironments. The dominant role of HIF2α in tumor biology is likely due to its selective activation of genes such as cyclin D1, TGFa, PDGFb, and OCT4 that are not regulated by HIF1α. The mechanism through which the highly conserved HIF1 and HIF2 regulate distinct target genes has not been established. We have previously shown that the transcriptional domain, but not the DNA binding domain of HIF determines its target gene specificity, suggesting that HIFs achieve their target gene specificity by interacting with other transcriptional factors or cofactors via their transactivation domains. Here we reported that HIF2α achieves its target gene specificity and enhanced transcriptional activity by interacting with the b/HLH/LZ transcription factor USF2 (upstream stimulatory factor 2) on promoters of HIF2α specific genes. We observed that siRNA-mediated USF2 knockdown significantly inhibited hypoxic induction of HIF2α (but not HIF1α) target genes in Hep3B and RCC4T cells. Additionally, overexpression of a USF2 dominant negative construct in Hep3B cells significantly reduced the levels of HIF2α (but not HIF1α) target genes under hypoxia. These data determined that USF2 is required for HIF2α to activate its target gene under hypoxia. By HIF2 target gene promoter functional analysis, gel-shift, and Chromatin-IP, we found that USF2 enhances HIF2α transcriptional activity by binding to HIF2α specific gene promoters and recruiting co-activator CBP/P300. In summary, we have uncovered a novel function of USF2 in HIF2α target gene regulation and demonstrated that USF2 is required for HIF2, but not HIF1 to activate its target genes. This finding has laid a foundation for the development of specific HIF2α inhibitors for use in solid tumor treatment. NIH T32-GM08730; RO1 CA134687 NIH/NCI (Hu); Cancer League of Colorado (Hu) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2048. doi:10.1158/1538-7445.AM2011-2048