Abstract 119: Stabilization of hypoxia-inducible factor-1α by the human rhomboid family-1 gene product RHBDF1

Abstract

Abstract Hypoxia inducible factor 1α (HIF1α) is a key transcription factor in the maintenance of oxygen and energy homoeostasis. Increased levels of HIF1α in cancer cells are often associated with increased tumor angiogenesis, metastasis, drug resistance, and poor prognosis. We reported recently that the human rhomboid family-1 gene (RHBDF1) plays a critical role in facilitating tumor growth. Here, we show that RHBDF1 interacts with and stabilizes HIF1α. RHBDF1 gene-silencing with siRNA leads to markedly decreased HIF1α protein stability and down-regulation of HIF1α-targeted genes. However, HIF1α gene transcription and translation is unaffected. RACK1 and HSP90 are protein factors that compete for binding to HIF1α, causing either oxygen-independent degradation or stabilization of the latter. Protection of HIF1α from degradation by RHBDF1 is the result of a switch of HIF1α binding from RACK1 to HSP90. Stabilization of HIF1a can be abolished by using 17-allylaminogeldanamycin, an inhibitor of HSP90. Moreover, engineered over-expression of RHBDF1 leads to hypoxia-induced resistance of cancer cells to apoptosis-inducing agent Etoposide, an anticancer drug, apparently due to high HIF1α levels. These findings are consistent with the view that RHBDF1 may function as a chaperone to maintain HIF-1α stability. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 119.