Abstract 5323: Gene-specific DNA methylation alterations in non-alcoholic fatty liver disease (NAFLD)-derived hepatocellular carcinoma in mice
Authors: Barbara Borowa-Mazgaj, Aline de Conti, Mulugeta Seneshaw, Faridodin Mirshahi, Frederick A. Beland, Arun J. Sanyal, Igor P. Pogribny
Journal: Cancer Research (2018)

Abstract Hepatocellular carcinoma (HCC) ranks as one of the most aggressive human cancers, with a steadily increasing incidence in the United States and worldwide. HCC is a disease characterized by the presence of multiple heritable cellular, molecular, and metabolic abnormalities driven by genetic and epigenetic alterations. Among these abnormalities, cancer-related gene-specific cytosine DNA methylation alterations, which are potentially reversible, are of special interest. In the vast majority of patients, HCC develops in association with an underlying chronic liver disease, such as non-alcoholic fatty liver disease (NAFLD). In the present study, we investigated the role of gene-specific DNA methylation alterations in the transcriptomic deregulation in HCC and adjacent liver tissue samples from mice subjected to a diet-induced animal model of non-alcoholic fatty liver disease (DIAMOND)-derived liver carcinogenesis. A combined transcriptomic and gene-specific methylation analysis showed that the number of differentially expressed protein-coding genes, which can be regulated by epigenetic mechanisms, was 2.6-times greater in full-fledged HCC than in adjacent liver tissue, 181 and 69, respectively. This indicates that the development of HCC is characterized by a progressive accumulation of epigenetic abnormalities in tumor tissue. The extent of gene-specific DNA methylation varied among epigenetically-regulated differentially expressed genes; however, the number of down-regulated genes was markedly greater in full-fledged HCC. This was evidenced by the fact that only eight epigenetically down-regulated genes in adjacent tissue were in common with HCC. In contrast, in addition to these eight common genes, the expression of additional 35 genes was reduced in HCC. Analysis of gene-specific DNA methylation demonstrated an increase in DNA methylation of several carcinogenesis-related genes down-regulated in HCC, including Gnmt, Cbs, Egfr, Fgfr2, and Esr1. These genes were hypermethylated also in adjacent liver tissue. The hypermethylation and down-regulation of these genes in HCC were confirmed independently in the Stelic Animal Model (STAM) of derived liver carcinogenesis, another mouse model of NAFLD-associated hepatocarcinogenesis. These results demonstrate that the altered expression of key genes is mediated through aberrant DNA methylation and can be a mechanism contributing to the development of NAFLD-related HCC. Citation Format: Barbara Borowa-Mazgaj, Aline de Conti, Mulugeta Seneshaw, Faridodin Mirshahi, Frederick A. Beland, Arun J. Sanyal, Igor P. Pogribny. Gene-specific DNA methylation alterations in non-alcoholic fatty liver disease (NAFLD)-derived hepatocellular carcinoma in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5323.