Epigenetic regulation of OPA1 sensitizes hepatocellular carcinoma to sorafenib‐induced apoptosis (59.1)

Abstract

The aim of this study is to identify epigenetic markers of DNA methylation for the Optic Atrophy gene OPA1, which is an indication of Sorafenib sensitivity in HCC. Sorafenib has been shown to act as a multi‐kinase inhibitor in other cancers, and is used in the treatment of un‐resectable hepatocellular carcinoma (HCC). Patient response to this therapy is variable. We have previously shown that treatment with Sorafenib does not inhibit the AKT pathway in hepatocellular carcinoma cells and instead 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. We now show that 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.Grant Funding Source: NIH