Abstract B23: Epigenetic regulation of OPA1 sensitizes hepatocellular carcinoma to sorafenib-induced apoptosis

Abstract

Abstract Sorafenib is a multi-kinase inhibitor used in the treatment of un-resectable hepatocellular carcinoma (HCC). Patient response to this therapy is variable. In this study we show that treatment with Sorafenib induces rapid mitochondrial fragmentation, which is associated with the deregulation of mitochondria-fusion-related protein OPA1, thus inducing apoptosis. Exposure of HCC cells or isolated mitochondria to Sorafenib induces cytochrome c release. Our data indicate that siRNA-mediated OPA1 knockdown significantly sensitizes HCC cells to Sorafenib-induced apoptosis. Furthermore, Sorafenib inhibits HCC xenograft tumor growth in vivo, and does not induce apoptosis in healthy primary hepatocytes. Murine xenograft tumor tissue samples revealed mitochondria fusion protein OPA1 expression levels are strongly associated with the sensitivity of HCC to sorafenib treatment. We have shown that Sorafenib suppresses the tumorigenesis of HCC through the induction of mitochondrial injury via OPA1. Epigenetic analysis of the OPA1 gene promoter indicates a role for DNA methylation in the suppression of OPA1 expression, and a potential biomarker which can be utilized for the identification of patients whom may benefit from treatment with Sorafenib. Our results provide new insights into the pathogenesis of HCC and suggest that OPA1 is a novel therapeutic target in patients with HCC. Citation Format: William Matthew Puszyk, Hui-Jia Dong, Frank Zhao, Olorunseun Ogunwobi, Chen Liu. Epigenetic regulation of OPA1 sensitizes hepatocellular carcinoma to sorafenib-induced apoptosis. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr B23.