Differentiation Therapy by Epigenetic Reconditioning Exerts Antitumor Effects on Liver Cancer Cells

• Published in: Molecular therapy Vol. 26; no. 7; pp. 1840 - 1854
• Main Authors: Gailhouste, Luc, Liew, Lee Chuen, Yasukawa, Ken, Hatada, Izuho, Tanaka, Yasuhito, Nakagama, Hitoshi, Ochiya, Takahiro
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05-07-2018; Elsevier Limited; American Society of Gene & Cell Therapy
• Subjects: 5-azacytidine; Animals; Antitumor activity; Azacitidine - pharmacology; Azacytidine; Carcinogenesis - drug effects; Carcinogenesis - genetics; Carcinogenesis - pathology; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cell growth; Cell Line, Tumor; CpG islands; Cytotoxicity; Demethylation; Deoxyribonucleic acid; DNA; DNA methylation; DNA Methylation - drug effects; DNA Methylation - genetics; DNA methyltransferase; DNMT1 protein; Drug dosages; drug resistance; Enzymes; Epigenesis, Genetic - drug effects; Epigenesis, Genetic - genetics; epigenetic reconditioning; Epigenetics; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Gene silencing; Hep G2 Cells; hepatic differentiation; Hepatitis; Hepatocellular carcinoma; Hepatocytes; Hepatocytes - drug effects; Hepatocytes - pathology; Humans; Liver - drug effects; Liver - pathology; Liver cancer; Liver diseases; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Medical prognosis; Mice; Mice, Nude; Original; Phenotypes; R&D; Research & development; Solid tumors; tumor growth; Tumorigenesis; Tumorigenicity; Tumors; Japan; hepatic differentiation; 5-azacytidine; DNA methylation; tumor growth; drug resistance; epigenetic reconditioning; hepatocellular carcinoma
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2018.04.018

Primary liver tumors are mainly represented by hepatocellular carcinoma (HCC), one of the most aggressive and resistant forms of cancer. Liver tumorigenesis is characterized by an accumulation of epigenetic abnormalities, leading to gene extinction and loss of hepatocyte differentiation. The aim of this work was to investigate the feasibility of converting liver cancer cells toward a less aggressive and differentiated phenotype using a process called epigenetic reconditioning. Here, we showed that an epigenetic regimen with non-cytotoxic doses of the demethylating compound 5-azacytidine (5-AZA) promoted an anti-cancer response by inhibiting HCC cell tumorigenicity. Furthermore, epigenetic reconditioning improved sorafenib response. Remarkably, epigenetic treatment was associated with a significant restoration of differentiation, as attested by the increased expression of characteristic hepatocyte markers in reconditioned cells. In particular, we showed that reexpression of these epigenetically silenced liver genes following 5-AZA treatment or after knockdown of DNA methyltransferase 1 (DNMT1) was the result of regional CpG demethylation. Lastly, we confirmed the efficacy of HCC differentiation therapy by epigenetic reconditioning using an in vivo tumor growth model. In summary, this work demonstrates that epigenetic reconditioning using the demethylating compound 5-AZA shows therapeutic significance for liver cancer and is potentially attractive for the treatment of solid tumors.
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Curative management of primary liver cancer is limited given its resistance to chemotherapies. In this issue of Molecular Therapy, Gailhouste and colleagues show that demethylating agent-based treatments have anti-cancer effects on hepatic tumor cells, which supports the development of alternative epigenetic differentiation therapies to attenuate the aggressiveness and drug resistance of solid tumors.