Integrative Analysis Reveals Therapeutic Targets To The Dna Methyltransferase Inhibitor Sgi-110 In Hepatocellular Carcinoma

Abstract Objective There is an urgent need for developing more effective therapies for Hepatocellular carcinoma (HCC) because of its aggressiveness. Guadecitabine (SGI-110) is a second-generation DNA methyltransferase inhibitor (DNMTi) currently in clinical trials for HCC and shows greater stability and performance over first generation DNMTi. The aim of this study is to identify potential therapeutic targets of SGI-110 for clinical trials. Design HCC cell lines (SNU398, HepG2 and SNU475) were used to evaluate effects of SGI-110 by an integrative analysis of DNA methylation, nucleosome accessibility and gene expression profiles following the transient SGI-110 treatment and its clinic relevant by comparing HCC clinic data from TCGA. Results These HCC cell lines represent the three DNA methylation subtypes of primary HCC tumors based on TCGA data. After SGI-110 treatment, all cell lines were sensitive to SGI-110 with prolonged anti-proliferation effects. Up-regulated genes including tumor suppressors were positively correlated with nucleosome accessibility and negatively correlated with gene promoter DNA methylation, while the down-regulated genes, such as oncogenes, were negatively correlated with nucleosome accessibility and positively correlated with gene body DNA methylation. Furthermore, SGI-110 down-regulated PRC2 complex genes by demethylating their gene bodies, resulting in re-activation of PRC2 repressed gene promoters which are independent on DNA methylation. In addition, SGI-110 up-regulated endogenous retroviruses (ERVs) to reactivate immune pathways. Finally, about 45% of frequently altered genes in primary HCC tumors can be re-shaped into a “normal like” expression status through the treatment. Conclusion Our integrative analysis has successfully linked the anti-tumor effects of SGI-110 to detailed epigenetic alterations in HCC cells and identified potential therapeutic targets. We also provide rationale of combination treatment with immune checkpoint therapies. Citation Format: Minmin Liu, Toshinori Hinoue, Wanding Zhou, Hitoshi Ohtani, Anthony El-Khoueiry, John Daniels, Casey O'Connell, Tanya B. Dorff, Daniel J. Weisenberger, Gangning Liang. Integrative analysis reveals therapeutic targets to the DNA methyltransferase inhibitor SGI-110 in hepatocellular carcinoma [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 779.