Abstract
Abstract
The induction of hypoxia inducible factors (HIFs) is essential for the adaptation of tumor cells to a low oxygen environment. We found that the expression of the apoptosis inhibitor ARC was induced by hypoxia in a variety of cancer cell types and its induction is primarily HIF1 dependent. Chromatin immunoprecipitation (ChIP) and reporter assays also indicate that the ARC gene is regulated by direct binding of HIF1 to a hypoxia response element (HRE) located at -190 bp upstream of the transcription start site. HIFs play an essential role in the pathogenesis of renal cell carcinoma (RCC) under normoxic conditions, through the loss of the Von Hippel Lindau (VHL) gene. Accordingly, our results show that ARC is not expressed in normal renal tissue, but is highly expressed in 65% of RCC tumors, which also express high levels of Carbonic Anhydrase IX (CAIX), a HIF1-dependent gene. Compared to controls, ARC-deficient RCCs exhibited decreased colony formation and increased apoptosis in vitro. In addition, loss of ARC resulted in a dramatic reduction of RCC tumor growth in SCID mice in vivo. Thus, HIF-mediated increased expression of ARC in RCC can explain how loss of VHL can promote survival early in tumor formation.
Citation Format: Olga V. Razorenova, Laura Castellini, Renata Colavitti, Laura E. Edgington, Monica Nicolau, Xin Huang, Barbara Bedogni, Edward M. Mills, Matthew Bogyo, Amato J. Giaccia. The Apoptosis repressor with a CARD domain (ARC) is a direct HIF1 target gene and promotes survival and proliferation of VHL deficient renal cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1181. doi:10.1158/1538-7445.AM2014-1181
