Project Description Hepatocellular carcinoma (HCC) is the fifth most common human cancer and the third leading cause of cancer-related death. The tumors usually develop in the background of chronic liver diseases with inflammation, tissue injury and disregulated hepatocyte regeneration. Recent whole-genome sequencing analyses have identified MALAT1 as a frequently mutated long noncoding RNA (lncRNA) in human HCC, although the mechanism by which MALAT1 regulates hepatic carcinogenesis remains unknown. The current application is proposed to investigate the biological functions and molecular mechanisms of MALAT1 in HCC. We hypothesize that MALAT1 is a pivotal long non-coding RNA that drives hepatic carcinogenesis through formation of a lncRNA- protein complex that terminates TGF-β/R-Smad signaling and through interaction with chromatin-modifying proteins thus regulating liver cancer gene expression. We further postulate that inhibition of MALAT1 and related signaling molecules may represent an effective therapeutic strategy for HCC treatment. These hypotheses will be evaluated by complementary in vitro biochemical and molecular analyses and in vivo animal models. We propose two interrelated specific aims. Specific Aim 1 is designed to delineate the effect and mechanism of MALAT1 in liver carcinogenesis. Experiments will be carried out to evaluate the hypothesis that MALAT1 promotes liver carcinogenesis through formation of a lncRNA-protein complex that facilitates Smad2/3 de-phosphorylation and thus termination of TGF-β/R-Smad signaling. Studies will also be performed to examine MALAT1 interaction with the H3K36 methyltransferase SETD2 and other chromatin-modifying proteins. In Specific Aim 2, we will assess the therapeutic efficacy of inhibiting MALAT1 for HCC treatment in preclinical models. The proposed studies will further define the molecular mechanisms of hepatic carcinogenesis and provide important implication for development of novel target therapies.