Elucidation of epigenetic regulation of hepatitis B virus replication and its therapeutic application

• Project/Area Number: 26460985
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: The University of Tokyo
• Principal Investigator: TANAKA YASUO 東京大学, 医学部附属病院, 助教 (40422290)
• Co-Investigator(Kenkyū-buntansha): 立石 敬介 東京大学, 医学部附属病院, 講師 (20396948) ; 建石 良介 東京大学, 医学部附属病院, 特任講師 (50444089)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: HBV / エピジェネティクス / cccDNA / ヒストンアセチル化 / HBV再活性化 / 再活性化

Outline of Final Research Achievements

We investigated the mechanisms of epigenetic regulation and modification of cccDNA. In HepG 2.2.15 cells, acetylation of histones H3 and H4 in the HBV core promoter region was observed. Dexamethasone treatment enhanced HBV replication by inducing hyperacetylation of histones in the HBV core promoter region. Furthermore, active recruitment of histone acetyltransferases in core promoter region was observed. One of the histone acetyltransferase inhibitors, CPTH2 (GCN5 inhibitor),reduced HBV pgRNA transcription and cancelled transcriptional activation induced by dexamethasone. Our findings may assist in the development of novel effective therapy against HBV.

Research Products

• [Journal Article] Sharpin promotes hepatocellular carcinoma progression via transactivation of Versican expression. (2016)
  • Author(s): Tanaka Y, Tateishi K, Nakatsuka T, Kudo Y, Takahashi R, Miyabayashi K, Yamamoto K, Asaoka Y, Ijichi H, Tateishi R, Shibahara J, Fukayama M, Ishizawa T, Hasegawa K, Kokudo N, Koike K.
  • Journal Title: Oncogenesis. Volume: 5 Issue: 12 Pages: e277-e277
  • DOI: 10.1038/oncsis.2016.76
  • Peer Reviewed / Open Access
• [Journal Article] Stromal remodeling by the BET bromodomain inhibitor JQ1 suppresses the progression of human pancreatic cancer (2016)
  • Author(s): Yamamoto K, Tateishi K, Kudo Y, Hoshikawa M, Tanaka M, Nakatsuka T, Fujiwara H, Miyabayashi K, Takahashi R, Tanaka Y, Ijichi H, Nakai Y,Isayama H, Morishita Y, Aoki T, Sakamoto Y, Hasegawa K, Kokudo N, Fukayama M, Koike K.
  • Journal Title: Oncotarget Volume: 7 Issue: 38 Pages: 61469-61484
  • DOI: 10.18632/oncotarget.11129
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A potent therapeutics for gallbladder cancer by combinatorial inhibition of the MAPK and mTOR signaling networks. (2016)
  • Author(s): Mohri D, Ijichi H, Miyabayashi K, Takahashi R, Kudo Y, Sasaki T, Asaoka Y, Tanaka Y, Ikenoue T, Tateishi K, Tada M, Isayama H, Koike K.
  • Journal Title: Journal of Gastroenterology Volume: 印刷中 Issue: 7 Pages: 711-21
  • DOI: 10.1007/s00535-015-1145-1
  • Peer Reviewed / Open Access
• [Journal Article] Sarcopenia, Intramuscular Fat Deposition, and Visceral Adiposity Independently Predict the Outcomes of Hepatocellular Carcinoma (2015)
  • Author(s): Fujiwara N, Nakagawa H, Kudo Y, Tateishi R, Taguri M, Watadani T, Nakagomi R, Kondo M, Nakatsuka T, Minami T, Sato M, Uchino K, Enooku K, Kondo Y, Asaoka Y, Tanaka Y, Ohtomo K, Shiina S, Koike K
  • Journal Title: J Hepatol Volume: 62 Issue: 1 Pages: 131-140
  • DOI: 10.1016/j.jhep.2015.02.031
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Loss of histone demethylase KDM6B enhances aggressiveness of pancreatic cancer through downregulation of C/EBPα. (2014)
  • Author(s): Yamamoto K, Tateishi K, Kudo Y, Sato T, Yamamoto S, Miyabayashi K, Asaoka Y, Ijichi H, Hirata Y, Otsuka M, Nakai Y, Isayama H, Ikenoue T, Kurokawa M, Fukayama M, Kokudo N, Omata M and Koike K.
  • Journal Title: Carcinogenesis Volume: 35 Issue: 11 Pages: 2404-14
  • DOI: 10.1093/carcin/bgu136
  • Peer Reviewed / Open Access
• [Presentation] グルココルチコイドによるエピジェネティクスを介したHBV複製制御メカニズムの解 析 (2015)
  • Author(s): 田中 康雄、立石 敬介、中塚 拓馬、工藤 洋太郎、浅岡 良成、堤 武也、小池 和彦
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: 熊本
  • Year and Date: 2015-05-21 – 2015-05-22
• [Presentation] グルココルチコイドによるエピジェネティクスを介したHBV複製制御メカニズムの解析 (2015)
  • Author(s): 田中康雄、立石敬介、中塚拓馬、工藤洋太郎、浅岡良成、堤武也、小池和彦
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: ホテル日航熊本(熊本県・熊本市)
  • Year and Date: 2015-05-21
• [Presentation] Hepatitis B virus transcription is enhanced with glucocorticoid through the acetylation of covalently closed circular DNA bound histones (2014)
  • Author(s): Yasuo Tanaka, Keisuke Tateishi, Takeya Tsutsumi, Kazuhiko Koike.
  • Organizer: The 11th JSH Single Topic Conference
  • Place of Presentation: Hiroshima, JAPAN
  • Year and Date: 2014-11-20 – 2014-11-21