Analysis of epigenetic changes in hepatocellular carcinoma and an investigation for a new therapeutic modality targeting histone acetylation

• Project/Area Number: 24590993
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Keio University
• Principal Investigator: SAITO Hidetsugu 慶應義塾大学, 薬学部, 教授 (80186949)
• Co-Investigator(Renkei-kenkyūsha): MASHINO Tadahiko 慶應義塾大学, 薬学部, 教授 (90165697) ; SAITO Yoshimasa 慶應義塾大学, 薬学部, 准教授 (90360114)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: エピゲノム変化 / ヒストン脱アセチル化酵素阻害薬 / microRNA / C型肝炎ウイルス / 肝細胞癌 / Nrf2 / EZH2 / 培養細胞株 / HCV / ヒストン修飾 / エピジェネティクス / マイクロRNA / レプリコン細胞 / osteopontin / apolipoprotein-A1 / miR-122 / スベロイルアニリドヒドロキサム酸 / トリコマイシンA

Outline of Final Research Achievements

The aim of this study was to investigate a new therapeutic strategy against hepatocellular carcinoma (HCC) and viral infection using epigenetic changes especially by the histone modifier. Cell lines infected with hepatitis C virus (HCV) or replicons were used in this study. Histone deacetylase inhibitor (HDACi), SAHA, inhibited HCV replication by changing host cellular gene expressions as well as decreasing cellular proliferation by inhibiting EZH2 expression. Nrf2 expression was important for long-term HCV infection in the cell line, and expression levels of Nrf2, EZH2 and miR-122 mutually affect proliferation of cells and also HCV.

Research Products

• [Journal Article] Free cholesterol accumulation in hepatic stellate cells: Mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice (2014)
  • Author(s): Tomita, K. Teratani, T. Suzuki, T. Shimizu, M. Sato, H. Narimatsu, K. Okada, Y. Kurihara, C. Irie, R. Yokoyama, H. Shimamura, K. Usui, S. Ebinuma, H. Saito, H. Watanabe, C. Komoto, S. Kawaguchi, A. Nagao, S. Sugiyama, K. Hokari, R. Kanai, T. Miura, S. Hibi, T.
  • Journal Title: Hepatology Volume: 59 Issue: 1 Pages: 154-169
  • DOI: 10.1002/hep.26604
  • Peer Reviewed
• [Journal Article] Acyl-CoA:cholesterol acyltransferase 1 mediates liver fibrosis by regulating free cholesterol accumulation in hepatic stellate cells. (2014)
  • Author(s): Tomita K, Teratani T, Suzuki T, Shimizu M, Sato H, Narimatsu K, Usui S, Furuhashi H, Kimura A, Nishiyama K, Maejima T, Okada Y, Kurihara C, Shimamura K, Ebinuma H, Saito H, Yokoyama H, Watanabe C, Komoto S, Nagao S, Sugiyama K, Aosasa S, Hatsuse K, Yamamoto J, Hibi T, Miura S, Hokari R, Kanai T.
  • Journal Title: Journal of Hepatology Volume: 印刷中 Issue: 1 Pages: 98-106
  • DOI: 10.1016/j.jhep.2014.03.018
  • Peer Reviewed
• [Journal Article] Prominent steatosis with hypermetabolism of the cell line permissive for years of infection with hepatitis C virus (2014)
  • Author(s): Sugiyama, K. Ebinuma, H. Nakamoto, N. Sakasegawa, N. Murakami, Y. Chu, P. S. Usui, S. Ishibashi, Y. Wakayama, Y. Taniki, N. Murata, H. Saito, Y. Fukasawa, M. Saito, K. Yamagishi, Y. Wakita, T. Takaku, H. Hibi, T. Saito, H. Kanai, T.
  • Journal Title: PLoS ONE Volume: 9 Issue: 4 Pages: 849-854
  • DOI: 10.1371/journal.pone.0094460
  • Peer Reviewed / Open Access
• [Journal Article] Silencing of microRNA-122 is an early event during hepatocarcinogenesis from non-alcoholic steatohepatitis. (2014)
  • Author(s): Takaki Y, Saito Y, Takasugi A, Toshimitsu K, Yamada S, Muramatsu T, Kimura M, Sugiyama K, Suzuki H, Arai E, Ojima H, Kanai Y, Saito H.
  • Journal Title: Cancer Sci. Volume: 105 Issue: 10 Pages: 1254-1260
  • DOI: 10.1111/cas.12498
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Alterations of epigenetics and microRNA in hepatocellular carcinoma (2014)
  • Author(s): Saito Y, Hibino S, Saito H
  • Journal Title: Hepatol Res Volume: 44(1) Issue: 1 Pages: 31-42
  • DOI: 10.1111/hepr.12147
  • Peer Reviewed / Open Access
• [Journal Article] Inhibitors of enhancer of zeste homolog 2 (EZH2) activate tumor-suppressor microRNAs in human cancer cells (2014)
  • Author(s): Hibino S, Saito Y, Muramatsu T, Otani A, Kasai Y, Kimura M, Saito H
  • Journal Title: Oncogenesis Volume: 3 Issue: 5 Pages: e104-e104
  • DOI: 10.1038/oncsis.2014.17
  • Peer Reviewed / Open Access
• [Journal Article] Epigenetic Alterations and MicroRNA Misexpression in Cancer and Autoimmune Diseases : a Critical Review (2013)
  • Author(s): Saito Y, Saito H, Liang G, Friedman JM
  • Journal Title: Clin Rev Allergy Immunol Volume: 47 Issue: 2 Pages: 128-135
  • DOI: 10.1007/s12016-013-8401-z
  • Peer Reviewed / Open Access
• [Journal Article] Hepatitis C Virus Infection Induces Inflammatory Cytokines and Chemokines Mediated by the Cross Talk between Hepatocytes and Stellate Cells. (2013)
  • Author(s): Nishitsuji H, Funami K, Shimizu Y, Ujino S, Sugiyama K, Seya T, Takaku H, Shimotohno K.
  • Journal Title: J. Viol Volume: 87 Issue: 14 Pages: 8169-8178
  • DOI: 10.1128/jvi.00974-13
  • Peer Reviewed
• [Journal Article] Anti-influenza activity of C60 fullerene derivatives. (2013)
  • Author(s): Shoji M., Takahashi E., Hatakeyama D., IwaiY.,MoritaY.,Shirayama R.,Echigo N., Kido H., Nakamura S., Mashino T., Okutani T., Kuzuhara T.
  • Journal Title: PLoS ONE Volume: (in press) Issue: 6 Pages: e66337-e66337
  • DOI: 10.1371/journal.pone.0066337
  • Peer Reviewed
• [Journal Article] Suppressive Effect of the Histone Deacetylase Inhibitor, Suberoylanilide Hydroxamic Acid (SAHA), on Hepatitis C Virus Replication via Epigenetic Changes in Host Cells (2013)
  • Author(s): Sato, A., Saito, Y., Sugiyama, K., Sakasegawa, N., Muramatsu, T., Fukuda, S., Yoneya, M., Kimura, M., Ebinuma, H., Hibi, T., Saito, H
  • Journal Title: J Cell Biochem Volume: 印刷中 Issue: 9 Pages: 1987-1996
  • DOI: 10.1002/jcb.24541
  • Peer Reviewed
• [Journal Article] Role of CTCF in the regulation of microRNA expression (2012)
  • Author(s): Saito Y, Saito H
  • Journal Title: Front Genet Volume: 3 Pages: 186-186
  • DOI: 10.3389/fgene.2012.00186
  • Peer Reviewed
• [Journal Article] MicroRNAs in cancers and neurodegenerative disorders (2012)
  • Author(s): Saito Y, Saito H
  • Journal Title: Front Genet Volume: 3 Pages: 194-194
  • DOI: 10.3389/fgene.2012.00194
  • Peer Reviewed
• [Presentation] Epigenetic作用薬を用いたC型肝炎ウイルスの制御：ヒストン脱アセチル化阻害薬の有用性． (2013)
  • Author(s): 齋藤英胤、齋藤義正、杉山和夫．
  • Organizer: 第49回日本肝臓学会総会
  • Place of Presentation: 東京
• [Presentation] Nrf2/sMaf転写因子複合体はHCVによる肝細胞脂肪蓄積に関与する． (2013)
  • Author(s): 杉山和夫、海老沼浩利、酒瀬川典子、齋藤義正、金井隆典、日比紀文、齋藤英胤．
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] ヒストン修飾制御薬によるマイクロRNAを介した抗がん作用の検討． (2013)
  • Author(s): 日比野沙奈、齋藤義正、村松俊英、大谷亜希、笠井雄佑、植木里美、山田翔士、木村真規、齋藤英胤．
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] メタボローム・トランスクリプトーム統合的解析によるC型肝炎肝脂肪蓄積の機構解明． (2013)
  • Author(s): 杉山和夫、齋藤英胤、日比紀文．
  • Organizer: 第17回日本肝臓学会大会
  • Place of Presentation: 東京
• [Presentation] HCV感染細胞における転写因子Nrf2によって制御される遺伝子群の発現解析． (2013)
  • Author(s): 酒瀬川典子、杉山和夫、海老沼浩利、中本伸宏、村上優子、齋藤英胤、金井隆典．
  • Organizer: 第61回日本ウイルス学会学術集会
  • Place of Presentation: 神戸
• [Presentation] MiR-1246 and miR-302 are novel target of epigenetic therapy with DZNep and SAHA in human cancer cells. (2013)
  • Author(s): Hibino S, Saito Y, Muramatsu T, Otani A, Kasai Y, Kimura M, Saito H.
  • Organizer: Digestive Disease Week 2013
  • Place of Presentation: Orlando, USA
• [Presentation] ヒストン脱アセチル化酵素阻害薬suberoylanilide hydroxamic acid (SAHA)によるC型肝炎ウイルス（HCV）の増殖抑制効果． (2012)
  • Author(s): 佐藤郁美、齋藤義正、永見早耶花、酒瀬川典子、福田真也、木村真規、杉山和夫、海老沼浩利、齋藤英胤．
  • Organizer: 第48回日本肝臓学会総会
  • Place of Presentation: 金沢
• [Presentation] C型肝炎ウイルス持続感染培養肝細胞の樹立と応用． (2012)
  • Author(s): 杉山和夫、齋藤英胤、日比紀文．
  • Organizer: 第39回日本肝臓学会東部会
  • Place of Presentation: 東京
• [Presentation] Usefulness of long-term (over 2 years) cultured cell clone persistently and productively infected with chimeric HCV. (2012)
  • Author(s): Sugiyama K, Saito H, Ebinuma H, Sakasegawa N, Murakami Y, Nakamoto N, Usui S, Ishibashi Y, Chu P-S, Wakayama Y, Saito Y, Kanai T, Hibi T.
  • Organizer: 63th Annual Meeting of American Association for the Study of Liver Diseases (AASLD)
  • Place of Presentation: Boston, USA
• [Remarks] 慶應義塾大学 薬学部・薬学研究科 研究室紹介 薬物治療学
  • URL: http://www.pha.keio.ac.jp/research/pt/index.html
• [Remarks] 慶應義塾大学薬学部 大学院薬学研究科 研究室紹介 薬物治療学
  • URL: http://www.pha.keio.ac.jp/laboratory/laboratory16.html