Aberrant hydroxymethylation in human liver cancer

• Project/Area Number: 25860521
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: The University of Tokyo
• Principal Investigator: NAGAE Genta 東京大学, 先端科学技術研究センター, 特任講師 (10587348)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 肝臓病学 / エピジェネティクス / 肝臓学

Outline of Final Research Achievements

Methylation profiles of hepatocellular carcinoma (HCC) have revealed aberrant hypermethylation and hypomethylation, which form four subgroups. However, molecular significance of aberrant hypomethylation in HCC remains poorly understood. Here, we performed comprehensive profiling of cytosine methylation and hydroxymethylation (5-hmC) for the TET1-upregulated HCCs and clarified the aberrant deposition of 5-hmC in a genome-wide manner. Knockdown of endogenous TET1 in hepatoma cell lines decreased hmC deposition with cell growth suppression. Collectively, these results indicate the novel function of methylcytosine dioxygenase TET1 that promotes cell proliferation though epigenetic dysregulation of the oncogenic targets during hepatocarcinogenesis.

Research Products

• [Journal Article] Integrated multiregional analysis proposing a new model of colorectal cancer evolution (2016)
  • Author(s): R. Uchi (他40名, 山本36番目)
  • Journal Title: PLoS Genet Volume: 12 Pages: 1005778-1005778
  • DOI: 10.1371/journal.pgen.1005778
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Prognostic significance of CpG island methylator phenotype in surgically resected small cell lung carcinoma (2016)
  • Author(s): Saito Y, Nagae G, Motoi N, Miyauchi E, Ninomiya H, Uehara H, Mun M, Okumura S, Ohyanagi F, Nishio M, Satoh Y, Aburatani H, Ishikawa Y.
  • Journal Title: Cancer Sci Volume: 107(3) Pages: 320-325
  • DOI: 10.1111/cas.12876
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Integrated molecular analysis of adult T-cell leukemia/lymphoma. (2015)
  • Author(s): Kataoka K, Nagata Y, Kitanaka A, Shiraishi Y, Shimamura T, Yasunaga J, Totoki Y, Chiba K, Sato-Otsubo A, Nagae G, et al.
  • Journal Title: Nat Genet Volume: 47(11) Pages: 1304-1315
  • DOI: 10.1038/ng.3415
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Comparison of chemotherapeutic agents as a myeloablative conditioning with TBI for pediatric ALL: a study from the pediatric ALL working group of the JSHCT. (2015)
  • Author(s): Seki M, Nishimura R, Yoshida K, Shimamura T, Shiraishi Y, Sato Y, Kato M, Chiba K, Tanaka H, Hoshino N, Nagae G, Shiozawa Y, Okuno Y, Hosoi H, Tanaka Y, Okita H, Miyachi M, Souzaki R, Taguchi T, Koh K, Hanada R, Kato K, Nomura Y, Akiyama M, Oka A, Igarashi T, Miyano S, Aburatani H, Hayashi Y, Ogawa S, Takita J.
  • Journal Title: Pediatr Blood Cancer. Volume: 6 Pages: 1844-50
  • DOI: 10.1038/ncomms8557
  • NAID: 120005623266
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Age-Dependent Decrease of DNA Hydroxymethylation in Human T Cells (2015)
  • Author(s): Truong TP, Sakata-Yanagimoto M, Yamada M, Nagae G, Enami T, Nakamoto-Matsubara R, Aburatani H, Chiba S.
  • Journal Title: J Clin Exp Hematopathol Volume: 55(1) Issue: 1 Pages: 1-6
  • DOI: 10.3960/jslrt.55.1
  • NAID: 130005083797
  • Peer Reviewed / Open Access
• [Journal Article] GATA2 and secondary mutations in familial myelodysplastic syndromes and pediatric myeloid malignancies. (2015)
  • Author(s): Huang D, Nagata Y, Grossmann V, Radivoyevitch T, Okuno Y, Nagae G, et al.
  • Journal Title: Haematologica Volume: 100(8) Pages: 1051-1057
  • DOI: 10.3324/haematol.2014.111989
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] がん研究におけるシングルセル遺伝子解析 (2015)
  • Author(s): 永江玄太
  • Journal Title: 実験医学 2015年1月号 Vol.33 No.1 シングルセル生物学 Volume: 33 Pages: 7-14
• [Journal Article] Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. (2014)
  • Author(s): Totoki Y, Tatsuno K, Covington KR, Ueda H, Creighton CJ, Kato M, Tsuji S, Donehower LA, Slagle BL, Nakamura H, Yamamoto S, Shinbrot E, Hama N, Lehmkuhl M, Hosoda F, Arai Y, Walker K, Dahdouli M, Gotoh K, Nagae G, Gingras MC, Muzny DM, …, Takayama T, Fukayama M, Gibbs RA, Wheeler DA, Aburatani H, Shibata T
  • Journal Title: Nature Genetics Volume: 46 Pages: 1267-1273
  • DOI: 10.1038/ng.3126
  • Peer Reviewed
• [Journal Article] Hes1 promotes blast crisis in chronic myelogenous leukemia through MMP9 up-regulation in leukemic cells. (2014)
  • Author(s): Nakahara F, Kitaura J, Uchida T, Nishida C, Togami K, Inoue D, Matsukawa T, Kagiyama Y, Enomoto Y, Kawabata KC, Chen-Yi L, Komeno Y, Izawa K, Oki T, Nagae G, Harada Y, Harada H, Otsu M, Aburatani H, Heissig B, Hattori K, Kitamura T.
  • Journal Title: blood Volume: 123(25) Pages: 3932-3942
  • DOI: 10.1182/blood-2013-01-476747
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Methionine Metabolism Regulates Maintenance and Differentiation of Human Pluripotent Stem Cells. (2014)
  • Author(s): Shiraki, N., Shiraki, Y., Tsuyama, T., Obata, F., Miura, M., Nagae, G., Aburatani, H., Kume, K., Endo, F., and Kume, S.
  • Journal Title: Cell Metab. Volume: 19 Pages: 122-3
  • DOI: 10.1016/j.cmet.2014.03.017
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 全ゲノムメチル化解析からみえてきたがん細胞のメチル化異常 (2014)
  • Author(s): 永江玄太
  • Journal Title: 実験医学増刊 Vol.32 No.12 個別化医療を拓くがんゲノム研究 Volume: 32 Pages: 67-71
• [Journal Article] Concurrent activation of acetylation and tri-methylation of H3K27 in a subset of hepatocellular carcinoma with aggressive behavior. (2014)
  • Author(s): Hayashi A, Yamauchi N, Shibahara J, Kimura H, Morikawa T, Ishikawa S, Nagae G, Nishi A, Sakamoto Y, Kokudo N, Aburatani H, Fukayama M.
  • Journal Title: PLoS One Volume: 9
  • DOI: 10.1371/journal.pone.0091330
  • Peer Reviewed
• [Journal Article] H3F3A K27M mutations in thalamic gliomas from young adult patients. (2014)
  • Author(s): Aihara K, Mukasa A, Gotoh K, Saito K, Nagae G, Tsuji S, Tatsuno K, Yamamoto S, Takayanagi S, Narita Y, Shibui S, Aburatani H, Saito N
  • Journal Title: Neuro Oncology Volume: 16 Pages: 140-146
  • DOI: 10.1093/neuonc/not144
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. (2014)
  • Author(s): Haferlach T, Nagata Y, Grossmann V, Okuno Y, Bacher U, Nagae G, Schnittger S, Sanada M, Kon A, Alpermann T, Yoshida K, Roller A, Nadarajah N, Shiraishi Y, Shiozawa Y, Chiba K, Tanaka H, Koeffler HP, Klein HU, Dugas M, Aburatani H, Kohlmann A, Miyano S, Haferlach C, Kern W, Ogawa S.
  • Journal Title: Leukemia Volume: 28(2) Pages: 4241-247
  • DOI: 10.1038/leu.2013.336
  • Peer Reviewed
• [Journal Article] Integrated molecular analysis of clear-cell renalcell carcinoma (2014)
  • Author(s): Sato Y, Yoshida K
  • Journal Title: Nat Genet Volume: 45 Pages: 860-7
  • DOI: 10.1038/ng.2699
  • Peer Reviewed
• [Journal Article] A. Concurrent loss of Ezh2 and Tet2 cooperates in the pathogenesis of myelodysplastic disorders (2013)
  • Author(s): Muto T, Sashida G, Oshima M, Wendt GR, Mochizuki-Kashio M, Nagata Y, Sanada M, Miyagi S, Saraya A, Kamio A, Nagae G, Nakaseko C, Yokote K, Shimoda K, Koseki H, Suzuki Y, Sugano S, Aburatani H, Ogawa S, Iwama A.
  • Journal Title: J Exp Med. Volume: 210(12) Pages: 2627-2639
  • DOI: 10.1084/jem.20131144
  • Peer Reviewed
• [Journal Article] Recurrent mutations in multiple components of the cohesin complex inmyeloid neoplasms (2013)
  • Author(s): Kon A, Yoshida K
  • Journal Title: Nature Genetics Volume: 45 Pages: 1232-1237
  • DOI: 10.1038/ng.2731
  • Peer Reviewed
• [Journal Article] Histone demethylase KDM4C regulates sphere formation by mediating the cross talk between Wnt and Notch pathways in colonic cancer cells. (2013)
  • Author(s): Yamamoto S, Tateishi K, Kudo Y, Yamamoto K Isagawa T, Nagae G, Nakatsuka T, Asaoka Y, Ijichi H, Hirata Y, Otsuka M, Ikenoue T, Aburatani H, Omata M, Koike K
  • Journal Title: Carcinogenesis Volume: 34(10) Pages: 2380-8
  • DOI: 10.1093/carcin/bgt174
  • Peer Reviewed
• [Journal Article] The Role of NF-κB Signaling in the Maintenance of Pluripotency of Human Induced Pluripotent Stem Cells. (2013)
  • Author(s): Takase O, Yoshikawa M, Idei M, Hirahashi J, Fujita T, Takato T, Isagawa T, Nagae G, Suemori H, Aburatani H, Hishikawa K
  • Journal Title: PLoS One. Volume: 8(2)
  • DOI: 10.1371/journal.pone.0056399
  • Peer Reviewed
• [Presentation] 肝がんにおけるエンハンサー領域のエピゲノム異常 (2015)
  • Author(s): 永江玄太、Renard-Guillet Claire、辰野健二、山本尚吾、上田宏生、林玲匡、緑川泰、中川英刀、柴田龍弘、油谷浩幸
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県）
  • Year and Date: 2015-10-09
• [Presentation] TET1の発現上昇はエンハンサー領域の異常ヒドロキシメチル化を介して肝細胞癌の悪性形質を促進する (2015)
  • Author(s): 永江玄太、白井聖一、関元昭、工藤洋太郎、神尾明日香、緑川泰、立石敬介、一瀬雅夫、油谷浩幸
  • Organizer: 第9回エピジェネティクス研究会
  • Place of Presentation: 学術総合センター（東京都）
  • Year and Date: 2015-05-25
• [Presentation] TET1 promotes malignant characteristics by aberrant enhancer hydroxymethylation in hepatocellular carcinoma. (2015)
  • Author(s): Nagae G, Shirai K, Seki M, Kamio A, Midorikawa Y, Tateishi K, Ichinose M, Aburatani H.
  • Organizer: Keystone Symposia, DNA methylation
  • Place of Presentation: Keystone、USA
  • Year and Date: 2015-04-01
• [Presentation] Single cell transcriptome analysis of liver cancer stem cells (2014)
  • Author(s): Genta Nagae, Hiromitsu Ito, Shinji Tanaka, Hiroyuki Aburatani
  • Organizer: Keystone symposia
  • Place of Presentation: Banff, Canada
• [Presentation] TET1 promotes malignant characteristics by aberrant enhancer hydroxymethylation in hepatocellular carcinoma (2014)
  • Author(s): Genta Nagae, Hiroyuki Aburatani
  • Organizer: The 73th Japan Cancer Association Annual Meeting
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25
  • Invited
• [Presentation] Cytosine methylation dynamics during hepatic differentiation (2013)
  • Author(s): 永江玄太 ・ 白木伸明 ・神尾明日香 ・藤田隆教 ・粂昭苑・ 油谷浩幸
  • Organizer: 第7回エピジェネティクス研究会
  • Place of Presentation: 奈良
• [Presentation] Variable patterns of aberrant promoter methylation in clinical cancer tissues (2013)
  • Author(s): Genta Nagae, Shingo Tsuji, Hiroyuki Aburatani
  • Organizer: 第72回日本癌学会
  • Place of Presentation: 横浜
• [Remarks] 東京大学先端科学技術研究センター ゲノムサイエンス分野
  • URL: http://www.genome.rcast.u-tokyo.ac.jp/
• [Remarks] 東京大学先端科学技術研究センター
  • URL: http://www.rcast.u-tokyo.ac.jp/research/people/staff-nagae_genta_ja.html