Molecular pathology of SET-related histone methyltransferase in refractory cancer

• Project/Area Number: 16K08647
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Akiyama Yoshimitsu 東京医科歯科大学, 大学院医歯学総合研究科, 講師 (80262187)
• Co-Investigator(Kenkyū-buntansha): 田中 真二 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (30253420) ; 島田 周 東京医科歯科大学, 大学院医歯学総合研究科, 助教 (20609705)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: エピジェネティクス / エピゲノム / ヒストン修飾 / メチル化 / 難治性消化器癌 / SETドメイン / クロマチン免疫沈降法 / 難治性癌 / ヒストンメチル化

Outline of Final Research Achievements

We focused on alterations of histone methyltransferases with SET domain in refractory cancer. Overexpression of SETDB2 was detected in approximately 40% of gastric cancer (GC), and the GC patients with SETDB2 overexpression significantly showed worse prognosis. SETDB2 overexpression in GC cells accelerated cell growth and invasiveness, and suppressed the expression levels of WWOX and CADM1, tumor suppressor genes, through histone H3K9 trimethylation changes. These data suggest that SETDB2 has oncogenic roles and plays an important role in malignant progression of GC. Overexpression of PRMT6 and loss of KDM6A were detected in refractory cancer as well. Finally, we optimized the condition of chromatin immunoprecipitation assay for the primary cancer tissues.

Academic Significance and Societal Importance of the Research Achievements

エピゲノム研究分野において、ヒストン修飾異常の解析が進んでいる。SETDB1やEZH2などのSETドメイン含有酵素の異常が多くの癌で報告され、その阻害剤の研究が進んでいる。SETDB2に関しては全く不明であったが、本研究でSETDB2の高発現、および癌促進的が明らかになったことで、今後、この酵素に着目した治療薬の開発につながると期待できる。臨床検体におけるヒストン修飾解析は培養細胞株に比べて困難であったが、本研究でその条件設定を行い癌組織でもヒストン修飾変化を解析できるようになった。

Research Products

• [Int'l Joint Research] Peking University(China)
• [Int'l Joint Research] Seoul National University(韓国)
• [Journal Article] Loss of ARID1A Induces a Stemness Gene ALDH1A1 Expression With Histone Acetylation in the Malignant Subtype of Cholangiocarcinoma (2020)
  • Author(s): Yoshino J, Akiyama Y, Shimada S, Ogura T, Ogawa K, Ono H, Mitsunori Y, Ban D, Kudo A, Yamaoka S, Tanabe M, Tanaka S.
  • Journal Title: Carcinogenesis Volume: 0000 Pages: 0000-0000
  • DOI: 10.1093/carcin/bgz179
  • Peer Reviewed / Open Access
• [Journal Article] ヒストン修飾 (2020)
  • Author(s): 秋山好光
  • Journal Title: 週刊 医学のあゆみ Volume: 272 Pages: 10-16
• [Journal Article] Upregulation of cancer-associated gene expression in activated fibroblasts in a mouse model of non-alcoholic steatohepatitis (2019)
  • Author(s): Asakawa M, Itoh M, Suganami T, Sakai T, Kanai S, Shirakawa I, Yuan X, Hatayama T, Shimada S, Akiyama Y, Fujiu K, Inagaki Y, Manabe I, Yamaoka S, Yamada T, Tanaka S, Ogawa Y.
  • Journal Title: Sci. Rep. Volume: 9 Pages: 19601-19601
  • DOI: 10.1038/s41598-019-56039-0
  • Peer Reviewed / Open Access
• [Journal Article] Asymmetric dimethylation at histone H3 arginine 2 by PRMT6 in gastric cancer progression. (2019)
  • Author(s): Okuno K, Akiyama Y, Shimada S, Nakagawa M, Tanioka T, Inokuchi M, Yamaoka S, Kojima K, Tanaka S.
  • Journal Title: Carcinogenesis Volume: 40 Pages: 15-26
  • DOI: 10.1093/carcin/bgy147
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comprehensive molecular characterization of liver cancer and inheritance of the phenotypic traits during tumor recurrence. (2019)
  • Author(s): Shimada S, Mogushi K, Akiyama Y, Furuyama T, Watanabe S, Ogura T, Ogawa K, Ono H, Mitsunori Y, Ban D, Kudo A, Arii S, Tanabe M, Wands JR, Tanaka S.
  • Journal Title: EBioMedicine. Volume: 40 Pages: 457-470
  • DOI: 10.1016/j.ebiom.2018.12.058
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A subset of diffuse-type gastric cancer is susceptible to mTOR inhibitors and checkpoint inhibitors (2019)
  • Author(s): Fukamachi H., Kim S., K., Koh J., Lee H. S., Sasaki Y., Yamashita K., Nishikawaji T., Shimada S., Akiyama Y., Byeon S. J., Bae D. H., Okuno K., Nakagawa M., Tanioka T., Inokuchi M., Kawachi H., Tsuchiya K., Kojima K., Tokino T., Eishi Y., Kim Y. S., Kim W. H., Yuasa Y., Tanaka S.
  • Journal Title: J Exp Clin Cancer Res Volume: 38 Pages: 127-127
  • DOI: 10.1186/s13046-019-1121-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 膵神経内分泌腫瘍におけるDAXX/ATRX異常とクロマチン修飾変化. (2019)
  • Author(s): 上田浩樹、秋山好光、田中真二.
  • Journal Title: 肝胆膵 Volume: 78 Pages: 39-46
• [Journal Article] Identification of selective inhibitors for diffuse-type gastric cancer cells by screening of annotated compounds in preclinical models. (2018)
  • Author(s): Shimada S, Akiyama Y, Mogushi K, Ishigami-Yuasa M, Kagechika H, Nagasaki H, Fukamachi H, Yuasa Y, Tanaka S.
  • Journal Title: British Journal of Cancer Volume: - Pages: 972-984
  • DOI: 10.1038/s41416-018-0008-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fatty Acid Binding Protein 4 (FABP4) Overexpression in Intratumoral Hepatic Stellate Cells within Hepatocellular Carcinoma with Metabolic Risk Factors (2018)
  • Author(s): Chiyonobu N、Shimada S、Akiyama Y、Mogushi K、Itoh M、Akahoshi K、Matsumura S、Ogawa K、Ono H、Mitsunori Y、Ban D、Kudo A、Arii S、Suganami T、Yamaoka S、Ogawa Y、Tanabe M、Tanaka S
  • Journal Title: Am. J. Pathol. Volume: 188 Pages: 1213-1224
  • DOI: 10.1016/j.ajpath.2018.01.012
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tumor suppressor functions of DAXX through histone H3.3/H3K9me3 pathway in pancreatic NETs. (2018)
  • Author(s): Ueda H, Akiyama Y, Shimada S, Mogushi K, Serizawa M, Matsumura S, Mitsunori Y, Aihara A, Ban D, Ochiai T, Kudo A, Tanabe M, Tanaka S.
  • Journal Title: Endocrine-Related Cancer Volume: 25(6) Pages: 619-631
  • DOI: 10.1530/erc-17-0328
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Acquired resistance with epigenetic alterations under long-term anti-angiogenic therapy for hepatocellular carcinoma. (2017)
  • Author(s): Ohata Y, Akiyama Y, Shimada S, Mogushi K, Nakao K, Matsumura S, Aihara A, Mitsunori Y, Ban D, Ochiai T, Kudo A, Tanabe M, Tanaka S.
  • Journal Title: Mol Cancer Ther. Volume: in press Pages: 1155-1165
  • DOI: 10.1158/1535-7163.mct-16-0728
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Meeting Report of the Fifth International Cancer Epigenetics Conference in Beijing, China, October 2016 (2017)
  • Author(s): Gao D, Herman JG, Cui H, Jen J, Fuks F, Brock MV, Ushijima T, Croce C, Akiyama Y, Guo M.
  • Journal Title: Epigenomics Volume: 9 Pages: 937-941
  • DOI: 10.2217/epi-2017-0030
  • Open Access / Int'l Joint Research
• [Journal Article] ARID2 modulates DNA damage response in human hepatocellular carcinoma cells. (2017)
  • Author(s): Oba A, Shimada S, Akiyama Y, Nishikawaji T, Mogushi K, Ito H, Matsumura S, Aihara A, Mitsunori Y, Ban D, Ochiai T, Kudo A, Asahara H, Kaida A, Miura M, Tanabe M, Tanaka S.
  • Journal Title: J Hepatol. Volume: in press Pages: 942-951
  • DOI: 10.1016/j.jhep.2016.12.026
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Overexpression of histone methyltransferase SETDB2 acts an oncogene in gastric cancer. (2017)
  • Author(s): Nishikawaji T, Akiyama Y, Shimada S, Kojima K, Kawano T, Eishi Y, Yuasa Y, Tanaka S.
  • Journal Title: Oncotarget Volume: 7 Pages: 67251-67265
  • DOI: 10.18632/oncotarget.11625
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Overexpression of PRMT6 and histone H3 arginine 2 asymmetric dimethylation in gastric cancer (2019)
  • Author(s): Akiyama Y, Okuno K, Shimada S, Tanaka S
  • Organizer: 2019 Post-A3 Joint Symposium, Cancer Epigenetics and Cancer Stem Cell Biology
  • Int'l Joint Research
• [Presentation] 胃癌におけるヒストンアルギニンメチル化タンパク質PRMT6の高発現は予後と悪性度に関与する. (2019)
  • Author(s): 秋山 好光, 島田 周, 田中 真二.
  • Organizer: 第78回日本癌学会学術総会
  • Int'l Joint Research
• [Presentation] 肝細胞癌の分子生物学的および免疫学的分類. (2019)
  • Author(s): 島田 周, 秋山 好光, 田中 真二.
  • Organizer: 第78回日本癌学会学術総会
  • Int'l Joint Research
• [Presentation] 胃癌の増殖、進展におけるPRMT6高発現とヒストンH3アルギニンジメチル化の関与. (2019)
  • Author(s): 秋山 好光, 奥野 圭祐, 島田 周, 田中 真二.
  • Organizer: 第13回日本エピジェネティクス研究会年会.
• [Presentation] プレシジョン・メディシンの外科学への応用 ゲノム医療・ゲノム編集時代におけるプレシジョン免疫複合療法. (2019)
  • Author(s): 田中 真二, 島田 周, 秋山 好光, 大庭 篤志, 渡辺 秀一, 奥野 圭祐, 水野 裕貴, 上田 浩樹, 吉野 潤, 菅原 了子, 小倉 俊郎, 小川 康介, 光法 雄介, 小野 宏晃, 伴 大輔, 工藤 篤, 大久保 憲一, 小嶋 一幸, 絹笠 祐介, 田邉 稔.
  • Organizer: 第119回日本外科学会定期学術集会
• [Presentation] 肝細胞癌における高頻度変異および特異的免疫サブタイプの解明と免疫precision medicine への展開. (2018)
  • Author(s): 田中真二、大庭篤志、島田周、秋山好光、小川康介、小野宏晃、光法雄介、伴大輔、工藤篤、田邉稔.
  • Organizer: 第73 回日本消化器外科学会総会
• [Presentation] メタボリック関連肝癌の腫瘍内星細胞におけるFABP4 発現亢進の意義. (2018)
  • Author(s): 島田周, 千代延記道, 秋山好光, 田中真二.
  • Organizer: 第77 回日本癌学会学術総会
• [Presentation] 肝細胞癌においてDEPDC5 不活化はｐ 62 発現上昇を介してロイシン欠乏に対する抵抗性の獲得に寄与する. (2018)
  • Author(s): 水野裕貴、島田 周、秋山好光、渡辺秀一、相田知海、小川康介、小野宏晃、光法雄介、伴 大輔、工藤 篤、山岡昇司、田中真二、田邉 稔.
  • Organizer: 第77 回日本癌学会学術総会
• [Presentation] 膵内分泌腫瘍においてDAXX はヒストンH3.3/H3K9 トリメチル化を介して癌抑制因子として働く. (2018)
  • Author(s): 秋山好光, 島田周, 田邉稔, 田中真二.
  • Organizer: 第77 回日本癌学会学術総会
• [Presentation] 低分化型胃がんは、形成過程の異なる２つのクラスターに分類できる. (2018)
  • Author(s): 深町博史, 西川路武人, 島田周, 秋山好光, 湯浅保仁, 土屋輝一郎, 田中真二.
  • Organizer: 第77 回日本癌学会学術総会
• [Presentation] Molecular mechanisms of SETDB2 histone methyltransferase overexpression in gastric cancer. (2017)
  • Author(s): Akiyama Y, Nishikawaji T, Shimada S, Yuasa Y, Tanaka S
  • Organizer: 第76回日本癌学会総会
• [Presentation] 臨床で活用されているDNAメチル化診断技術とがんの早期発見・治療への期待 (2017)
  • Author(s): 秋山好光
  • Organizer: がん早期診断の最新技術と実用化セミナー
• [Presentation] Expression changes of the histone H3 lysine methyltransferase genes and their function in gastric cancer (2016)
  • Author(s): Akiyama Y, Nishikawaji T, Shimada S, Deng D, Kim WH, Zhu WG, Yuasa Y, Tanaka S.
  • Organizer: 5th International Cancer Epigenetics Meeting
  • Place of Presentation: Beijing, 中国
  • Year and Date: 2016-10-20
  • Int'l Joint Research / Invited
• [Presentation] Reduced expression of SET7/9, a histone mono-methyltransferase, is associated with gastric cancer progression (2016)
  • Author(s): Akiyama Y, Nishikawaji T, Shimada S, Sakamoto A, Yuasa Y, Tanaka S.
  • Organizer: 第75回日本癌学会総会
  • Place of Presentation: パシフィコ横浜, 横浜
  • Year and Date: 2016-10-06
• [Presentation] SETDB2 contributes to gastric cancer progression by deregulating the expression of tumor suppressor genes (2016)
  • Author(s): Nishikawaji T, Akiyama Y, Shimada S, Yuasa Y, Tanaka S.
  • Organizer: 第75回日本癌学会総会
  • Place of Presentation: パシフィコ横浜, 横浜
  • Year and Date: 2016-10-06
• [Presentation] Reduced expression and its function of SET7/9, a histone methyltransferase gene, in gastric cancer (2016)
  • Author(s): Akiyama Y, Nishikawaji T, Shimada S, Sakamoto A, Deng D, Kim WH, Zhu WG, Yuasa Y, Tanaka S.
  • Organizer: The 35th Sapporo International Cancer Symposium
  • Place of Presentation: ロイトン札幌, 札幌
  • Year and Date: 2016-06-24
  • Int'l Joint Research
• [Presentation] Expression changes of the histone methyltransferase genes, SETDB2, in gastric cancers (2016)
  • Author(s): Akiyama Y, Nishikawaji T, Shimada S, Yuasa Y, Tanaka S.
  • Organizer: 26th Seoul International Cancer Symposium
  • Place of Presentation: Seoul, 韓国
  • Year and Date: 2016-06-17
  • Int'l Joint Research
• [Presentation] マウス胃がん細胞株を用いたTwist1発現における複合的なエピゲノム制御機構の解明 (2016)
  • Author(s): 秋山好光、坂本鮎菜、島田周、湯浅保仁、田中真二.
  • Organizer: 第10回日本エピジェネティクス研究会年会
  • Place of Presentation: 千里ライフサイエンスセンター, 大阪
  • Year and Date: 2016-05-19
• [Presentation] 胃がんにおけるヒストンメチル化酵素SETDB2の標的遺伝子に対する発現制御機構 (2016)
  • Author(s): 西川路 武人, 秋山好光, 島田周, 湯浅保仁, 田中真二.
  • Organizer: 第10回日本エピジェネティクス研究会年会
  • Place of Presentation: 千里ライフサイエンスセンター, 大阪
  • Year and Date: 2016-05-19
• [Book] 疾患・病態検査・診断法の開発 (2017)
  • Author(s): 秋山好光（分担）
  • Total Pages: 489
  • Publisher: 技術情報協会
  • ISBN: 9784861046742