| RRC ID |
56029
|
| 著者 |
Gailhouste L, Liew LC, Yasukawa K, Hatada I, Tanaka Y, Nakagama H, Ochiya T.
|
| タイトル |
Differentiation Therapy by Epigenetic Reconditioning Exerts Antitumor Effects on Liver Cancer Cells.
|
| ジャーナル |
Mol Ther
|
| Abstract |
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.
|
| 巻・号 |
26(7)
|
| ページ |
1840-1854
|
| 公開日 |
2018-7-5
|
| DOI |
10.1016/j.ymthe.2018.04.018
|
| PII |
S1525-0016(18)30191-6
|
| PMID |
29759938
|
| PMC |
PMC6035736
|
| MeSH |
Animals
Azacitidine / pharmacology
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 Line, Tumor
DNA Methylation / drug effects
DNA Methylation / genetics
Epigenesis, Genetic / drug effects
Epigenesis, Genetic / genetics*
Female
Gene Expression Regulation, Neoplastic / drug effects
Gene Expression Regulation, Neoplastic / genetics
Hep G2 Cells
Hepatocytes / drug effects
Hepatocytes / pathology
Humans
Liver / drug effects
Liver / pathology
Liver Neoplasms / drug therapy
Liver Neoplasms / genetics*
Liver Neoplasms / pathology
Mice
Mice, Nude
|
| IF |
8.402
|
| 引用数 |
12
|
| リソース情報 |
| ヒト・動物細胞 |
HuH-7 |
