胃癌におけるクロマチン構造異常による癌化機構の解明

• Project/Area Number: 19KK0415
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research (A))
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 43050:Genome biology-related
• Research Institution: Chiba University
• Principal Investigator: 岡部 篤史 千葉大学, 健康疾患オミクスセンター, 特任准教授 (80778118)
• Project Period (FY): 2020 – 2024
• Project Status: Granted (Fiscal Year 2023)
• Budget Amount: ¥15,210,000 (Direct Cost: ¥11,700,000、Indirect Cost: ¥3,510,000)
• Keywords: クロマチン構造 / 胃癌 / エピゲノム

Outline of Research at the Start

胃癌におけるエピゲノム解析の専門家であり、高度なクロマチン構造解析技術を有するPatrick Tan教授との国際共同研究を行う。これにより胃癌細胞株やEBV感染過程におけるクロマチン構造異常を解明するだけでなく、胃癌臨床サンプルを用いたクロマチン構造異常の検証も可能となる。その成果はクロマチン構造異常がもたらす発癌機構を解明し、胃癌の新規治療・診断に向けた基盤データとなるだけでなく、転写制御研究の知見と臨床を橋渡しし、新たな治療概念を構築する独自性の高い研究となる。

Outline of Annual Research Achievements

本国際共同研究では、胃癌におけるクロマチン構造解析により、胃癌分子サブタイプとクロマチン構造異常との関連を明らかにし、癌化・癌悪性化メカニズムを解明する。新型コロナにより渡航が叶わなかったが、新たにEBV陰性胃癌臨床検体、EBV陽性胃癌臨床検体を用いたHi-C解析を進めた。また、胃癌Patientderived xenograft（PDX）を用いて全エクソン解析、RNA-seq解析、InfiniumによるDNAメチル化解析を進め、データを取得した。
同じ胃癌PDXサンプルを用いたHi-C解析、ChIP-seqによるヒストン修飾解析を進めるため、条件検討を進めている。

Current Status of Research Progress

3: Progress in research has been slightly delayed.

Reason

新型コロナウイルスの世界的な蔓延により、渡航が難しく、計画が大きく変更せざるを得なかった。当初渡航することで進める予定であった解析は、可能な範囲で国際共同研究を進めるため、国内で取得可能なデータの取得と解析を進めた。また、ZoomによるWeb会議によりディスカッションを進めている。

Strategy for Future Research Activity

これまでに取得した胃癌細胞株でのクロマチン構造解析データ、胃癌PDXサンプルでのクロマチン構造解析データを遺伝子変異、遺伝子発現、DNAメチル化データと統合的に解析を進める。また、新型コロナの状況も落ち着いたことから、シンガポール渡航を進め、胃癌臨床サンプルを用いたクロマチン構造のデータ取得と、統合解析を進めていきたい。

Research Products

• [Journal Article] Enhancer infestation drives tumorigenic activation of inactive B compartment in Epstein-Barr virus-positive nasopharyngeal carcinoma (2024)
  • Author(s): Mizokami Harue、Okabe Atsushi、Choudhary Ruchi、Mima Masato、Saeda Kenta、Fukuyo Masaki、Rahmutulla Bahityar、Seki Motoaki、Goh Boon-Cher、Kondo Satoru、Dochi Hirotomo、Moriyama-Kita Makiko、Misawa Kiyoshi、Hanazawa Toyoyuki、Tan Patrick、Yoshizaki Tomokazu、Fullwood Melissa Jane、Kaneda Atsushi
  • Journal Title: eBioMedicine Volume: 102 Pages: 105057-105057
  • DOI: 10.1016/j.ebiom.2024.105057
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chromatin activation with H3K36me2 and compartment shift in metastatic castration-resistant prostate cancer (2024)
  • Author(s): Kanaoka Sanji、Okabe Atsushi、Kanesaka Manato、Rahmutulla Bahityar、Fukuyo Masaki、Seki Motoaki、Hoshii Takayuki、Sato Hiroaki、Imamura Yusuke、Sakamoto Shinichi、Ichikawa Tomohiko、Kaneda Atsushi
  • Journal Title: Cancer Letters Volume: 588 Pages: 216815-216815
  • DOI: 10.1016/j.canlet.2024.216815
  • Peer Reviewed / Open Access
• [Journal Article] Aberrant Upregulation of RUNX3 Activates Developmental Genes to Drive Metastasis in Gastric Cancer (2024)
  • Author(s): Suda Kazuto、Okabe Atsushi、Matsuo Junichi、Chuang Linda Shyue Huey、Li Ying、Jangphattananont Nawaphat、Mon Naing Naing、Myint Khine Nyein、Yamamura Akihiro、So Jimmy Bok-Yan、Voon Dominic Chih-Cheng、Yang Henry、Yeoh Khay Guan、Kaneda Atsushi、Ito Yoshiaki
  • Journal Title: Cancer Research Communications Volume: 4 Issue: 2 Pages: 279-292
  • DOI: 10.1158/2767-9764.crc-22-0165
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Link of mRNA and rRNA Transcription by PUF60/FIR through TFIIH/P62 as a Novel Therapeutic Target for Cancer (2023)
  • Author(s): Kitamura Kouichi、Hoshino Tyuji、Okabe Atsushi、Fukuyo Masaki、Rahmutulla Bahityar、Tanaka Nobuko、Kobayashi Sohei、Tanaka Tomoaki、Shida Takashi、Ueda Mashiro、Minamoto Toshinari、Matsubara Hisahiro、Kaneda Atsushi、Ishii Hideshi、Matsushita Kazuyuki
  • Journal Title: International Journal of Molecular Sciences Volume: 24 Issue: 24 Pages: 17341-17341
  • DOI: 10.3390/ijms242417341
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comprehensive molecular phenotyping of<i>ARID1A</i>-deficient gastric cancer reveals pervasive epigenomic reprogramming and therapeutic opportunities (2023)
  • Author(s): Xu Chang、Huang Kie Kyon、Law Jia Hao、Chua Joy Shijia、Sheng Taotao、Flores Natasha M、Pizzi Melissa Pool、Okabe Atsushi、Kaneda Atsushi、Prabhakar Shyam、Mazur Pawel Karol、Ajani Jaffer A、Yeoh Khay Guan、So Jimmy Bok-Yan、Tan Patrick
  • Journal Title: Gut Volume: 0 Issue: 9 Pages: 1-13
  • DOI: 10.1136/gutjnl-2022-328332
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Tumorigenic activation around <scp>HPV</scp> integrated sites in head and neck squamous cell carcinoma (2023)
  • Author(s): Mima Masato、Okabe Atsushi、Hoshii Takayuki、Nakagawa Takuya、Kurokawa Tomoya、Kondo Satoru、Mizokami Harue、Fukuyo Masaki、Fujiki Ryoji、Rahmutulla Bahityar、Yoshizaki Tomokazu、Hanazawa Toyoyuki、Misawa Kiyoshi、Kaneda Atsushi
  • Journal Title: International Journal of Cancer Volume: 152 Issue: 9 Pages: 1847-1862
  • DOI: 10.1002/ijc.34439
  • Peer Reviewed / Open Access
• [Journal Article] Hi-C analysis to identify genome-wide chromatin structural aberration in cancer. (2023)
  • Author(s): Okabe A, Kaneda A.
  • Journal Title: Methods Mol Biol Volume: 2519 Pages: 127-140
  • DOI: 10.1007/978-1-0716-2433-3_15
  • ISBN: 9781071624326, 9781071624333
  • Peer Reviewed
• [Journal Article] [Chiba Medical Society Young Investigator Award Minireview] Epigenetic contribution to tumorigenesis of host cells by Epstein-Barr virus infection (2022)
  • Author(s): Fujii T, Okabe A, Kaneda A
  • Journal Title: Chiba medical journal Volume: 98E Issue: 1 Pages: 1-7
  • DOI: 10.20776/S03035476-98E-1-P1
  • NAID: 120007193772
  • URL: https://opac.ll.chiba-u.jp/da/curator/900120227/
  • Year and Date: 2022-02-10
  • Peer Reviewed
• [Journal Article] Repression of DERL3 via DNA methylation by Epstein-Barr virus latent membrane protein 1 in nasopharyngeal carcinoma (2022)
  • Author(s): Kondo S, Okabe A, Nakagawa T, Matsusaka K, Fukuyo M, Rahmutulla B, Dochi H, Mizokami H, Kitagawa Y, Kurokawa T, Mima M, Endo K, Sugimoto H, Wakisaka N, Misawa K, Yoshizaki T, Kaneda A.
  • Journal Title: Biochimica et Biophysica Acta - Molecular Basis of Disease Volume: 1869(2) Issue: 2 Pages: 166598-166598
  • DOI: 10.1016/j.bbadis.2022.166598
  • Peer Reviewed / Open Access
• [Journal Article] Oncofetal protein IGF2BP1 regulates IQGAP3 expression to maintain stem cell potential in cancer (2022)
  • Author(s): Myint Khine、Chuang Linda Shyue Huey、Teh Yu Xuan、Mawan Nur Astiana、Shi Edward Jizhong、Mok Michelle Meng Huang、Nuttonmanit Napat、Matsuo Junichi、Li Ying、Yang Henry、Okabe Atsushi、Kaneda Atsushi、Osato Motomi、So Jimmy Bok-Yan、Yong Wei Peng、Tan Patrick、Yeoh Khay Guan、Ito Yoshiaki
  • Journal Title: iScience Volume: 25 Issue: 10 Pages: 105194-105194
  • DOI: 10.1016/j.isci.2022.105194
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chromatin Rewiring by Mismatch Repair Protein MSH2 Alters Cell Adhesion Pathways and Sensitivity to BET Inhibition in Gastric Cancer (2022)
  • Author(s): Nargund Amrita M.、Xu Chang、Mandoli Amit、Okabe Atsushi、Fullwood Melissa J.、Teh Bin Tean、Bi Xuezhi、Kaneda Atsushi、Li Shang、Tan Patrick
  • Journal Title: Cancer Research Volume: 82 Issue: 14 Pages: 2538-2551
  • DOI: 10.1158/0008-5472.can-21-2072
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cinobufagin inhibits proliferation of acute myeloid leukaemia cells by repressing c-Myc pathway-associated genes (2022)
  • Author(s): Hirasaki Yoshiro、Okabe Atsushi、Fukuyo Masaki、Rahmutulla Bahityar、Mano Yasunobu、Seki Motoaki、Hoshii Takayuki、Namiki Takao、Kaneda Atsushi
  • Journal Title: Chemico-Biological Interactions Volume: 360 Pages: 109936-109936
  • DOI: 10.1016/j.cbi.2022.109936
  • Peer Reviewed
• [Journal Article] ARID1A loss-of-function induces CpG island methylator phenotype (2022)
  • Author(s): Yamada Harumi、Takeshima Hideyuki、Fujiki Ryoji、Yamashita Satoshi、Sekine Shigeki、Ando Takayuki、Hattori Naoko、Okabe Atsushi、Yoshikawa Takaki、Obama Kazutaka、Katai Hitoshi、Kaneda Atsushi、Ushijima Toshikazu
  • Journal Title: Cancer Letters Volume: 532 Pages: 215587-215587
  • DOI: 10.1016/j.canlet.2022.215587
  • Peer Reviewed / Open Access
• [Journal Article] 胃癌とエピジェネティクス異常 (2022)
  • Author(s): 岡部篤史、金田篤志
  • Journal Title: 病理と臨床 Volume: 40 Pages: 19-25
• [Journal Article] An integrative transcriptional logic model of hepatic insulin resistance (2021)
  • Author(s): Kitamoto Takumi、Kuo Taiyi、Okabe Atsushi、Kaneda Atsushi、Accili Domenico
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 118 Issue: 45
  • DOI: 10.1073/pnas.2102222118
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Activation of EHF via STAT3 phosphorylation by LMP2A in Epstein‐Barr virus‐positive gastric cancer (2021)
  • Author(s): Li Wenzhe、Okabe Atsushi、Usui Genki、Fukuyo Masaki、Matsusaka Keisuke、Rahmutulla Bahityar、Mano Yasunobu、Hoshii Takayuki、Funata Sayaka、Hiura Nobuhiro、Fukayama Masashi、Tan Patrick、Ushiku Tetsuo、Kaneda Atsushi
  • Journal Title: Cancer Science Volume: 112 Issue: 8 Pages: 3349-3362
  • DOI: 10.1111/cas.14978
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transcriptional dysregulation by aberrant enhancer activation and rewiring in cancer (2021)
  • Author(s): Okabe Atsushi、Kaneda Atsushi
  • Journal Title: Cancer Science Volume: 112 Issue: 6 Pages: 2081-2088
  • DOI: 10.1111/cas.14884
  • Peer Reviewed / Open Access
• [Journal Article] TET1 upregulation drives cancer cell growth through aberrant enhancer hydroxymethylation of HMGA2 in hepatocellular carcinoma. (2021)
  • Author(s): Shirai K, Nagae G, Seki M, Kudo Y, Kamio A, Hayashi A, Okabe A, Ota S, Tsutsumi S, Fujita T, Yamamoto S, Nakaki R, Kanki Y, Osawa T, Midorikawa Y, Tateishi K, Ichinose M, Aburatani H.
  • Journal Title: Cancer Sci. Volume: 112 Issue: 7 Pages: 2855-2869
  • DOI: 10.1111/cas.14897
  • Peer Reviewed / Open Access
• [Journal Article] Cross-species chromatin interactions drive transcriptional rewiring in Epstein-Barr virus-positive gastric adenocarcinoma (2020)
  • Author(s): Okabe Atsushi, Huang Kie Kyon, Matsusaka Keisuke, Fukuyo Masaki, Xing Manjie, Ong Xuewen, Hoshii Takayuki, Usui Genki, Seki Motoaki, Mano Yasunobu, Rahmutulla Bahityar, Kanda Teru, Suzuki Takayoshi, Rha Sun Young, Ushiku Tetsuo, Fukayama Masashi, Tan Patrick, Kaneda Atsushi
  • Journal Title: Nature Genetics Volume: 52 Issue: 9 Pages: 919-930
  • DOI: 10.1038/s41588-020-0665-7
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Epstein‐Barr virus positive gastric cancer involves enhancer activation through ATF3 (2020)
  • Author(s): Asakawa Yuta、Okabe Atsushi、Fukuyo Masaki、Li Wenzhe、Ikeda Eriko、Mano Yasunobu、Funata Sayaka、Namba Hiroe、Fujii Takahiro、Kita Kazuko、Matsusaka Keisuke、Kaneda Atsushi
  • Journal Title: Cancer Science Volume: 00 Issue: 5 Pages: 1-11
  • DOI: 10.1111/cas.14370
  • Peer Reviewed / Open Access
• [Presentation] Chromatin structural aberrations induced by oncovirus infection (2023)
  • Author(s): 岡部篤史
  • Organizer: 第82回日本癌学会総会
  • Invited
• [Presentation] The virus-host genomic interactions drive heterochromatin disruption and oncogenic activation of enhancers (2023)
  • Author(s): Atsushi Okabe, Takahiro Fujii, Harue Mizokami, Keisuke Matsusaka, Masaki Fukuyo, Bahityar Rahmutulla, Patrick Tan, Hironori Yoshiyama, Atsushi Kaneda
  • Organizer: 第16回エピジェネティクス研究会年会
• [Presentation] 癌ウイルス感染が誘導するクロマチン構造異常 (2023)
  • Author(s): 岡部篤史, 藤井貴大、溝上晴恵、松坂恵介、福世真樹、Bhityar Rahmutulla、Patrick Tan、金田篤志
  • Organizer: 第34回日本消化器癌発生学会総会
• [Presentation] Chromatin structural alteration induced by oncovirus infection aberrantly activate transcriptional regulation (2023)
  • Author(s): Atsushi Okabe, Takahiro Fujii, Harue Mizokami, Keisuke Matsusaka, Masaki Fukuyo, Bahityar Rahmutulla, Patrick Tan, Hironori Yoshiyama, Atsushi Kaneda
  • Organizer: 第46回日本分子生物学会年会
• [Presentation] Oncovirus infection induces 3D chromatin structural aberrations (2022)
  • Author(s): Atsushi Okabe
  • Organizer: 第45回分子生物学会年会
  • Invited
• [Presentation] Analysis of chromatin structural aberrations in Epstein-Barr virus (+) Burkitt lymphoma (2022)
  • Author(s): Atsushi Okabe, Takahiro Fujii, Masaki Fukuyo, Bahityar Rahmutulla, Hironori Yoshiyama, Patrick Tan, Atsushi Kaneda
  • Organizer: 20th International Symposium on Epstein-Barr virus and Associated Diseases
  • Int'l Joint Research
• [Presentation] Analysis of chromatin structural aberrations in Epstein-Barr virus (+) Burkitt lymphoma (2022)
  • Author(s): Atsushi Okabe, Takahiro Fjii, Keisuke Matsusaka, Masaki Fukuyo, Bahityar Rahmutulla, Patrick Tan, Atsushi Kaneda
  • Organizer: 第15回日本エピジェネティクス研究会
• [Presentation] Analysis of chromatin structural aberrations induced by oncovirus infection (2022)
  • Author(s): Atsushi Okabe, Takahiro Fujii, Masaki Fukuyo, Bahityar Rahmutulla, Hironori Yoshiyama, Patrick Tan, Atsushi Kaneda
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] Chromatin structural alteration induced by oncovirus infection aberrantly activate transcriptional regulation (2021)
  • Author(s): Atsushi Okabe, Kie Kyon Huang, Keisuke Matsusaka, Masaki Fukuyo, Takayuki Hoshii, Bahityar Rahmutulla, Genki Usui, Teru Kanda, Tetsuo Ushiku, Masashi Fukayama, Patrick Tan, Atsushi Kaneda
  • Organizer: 第44回日本分子生物学会年会
  • Invited
• [Presentation] Tissue-wide analysis of chromatin structural aberrations induced by oncovirus infection (2021)
  • Author(s): Atsushi Okabe, Takahiro Fjii, Harue Mizokami, Keisuke Matsusaka, Masaki Fukuyo, Bahityar Rahmutulla, Patrick Tan, Atsushi Kaneda
  • Organizer: 第80回日本癌学会学術総会
• [Presentation] Heterochromatin rewiring by oncovirus infection through the novel mechanism ”enhancer infestation” in gastric adenocarcinoma (2021)
  • Author(s): Atsushi Okabe, Kie Kyon Huang, Keisuke Matsusaka, Masaki Fukuyo, Takayuki Hoshii, Genki Usui, Motoaki Seki, Yasunobu Mano, Bahityar Rahmutulla, Teru Kanda, Takayoshi Suzuki, Tetsuo Ushiku, Masashi Fukayama, Patrick Tan, Atsushi Kaneda
  • Organizer: 第80回日本癌学会学術総会
  • Invited
• [Presentation] Heterochromatin disruption and chromatin structural rewiring induced by Epstein-Barr virus infection in gastric adenocarcinoma (2021)
  • Author(s): Atsushi Okabe, Kie Kyon Huang, Keisuke Matsusaka, Masaki Fukuyo, Takayuki Hoshii, Bahityar Rahmutulla, Genki Usui, Teru Kanda, Tetsuo Ushiku, Masashi Fukayama, Patrick Tan, Atsushi Kaneda
  • Organizer: 19th International Symposium on Epstein-Barr Virus and associated diseases
  • Int'l Joint Research
• [Presentation] ウイルスがもたらすヘテロクロマチン破綻と 新たなエピジェネティック発癌機構「エンハンサー侵襲」の発見 (2021)
  • Author(s): 岡部篤史、Kie Kyon Huang、松坂恵介、福世真樹、星居孝之、臼井源紀、 関元昭、眞野恭伸、Bahityar Rahmutulla、神田輝、鈴木孝禎、牛久哲男、 深山正久、Patrick Tan、金田篤志
  • Organizer: 第14回日本エピジェネティクス研究会年会
  • Invited
• [Presentation] CHROMATIN REWIRING BY ONCOVIRUS INFECTION THROUGH THE NOVEL MECHANISM ”ENHANCER INFESTATION” IN GASTRIC ADENOCARCINOMA (2021)
  • Author(s): Atsushi Okabe, Kie Kyon Huang, Keisuke Matsusaka, Masaki Fukuyo, Takayuki Hoshii, Bahityar Rahmutulla, Manjie Xing, Xuewen Ong, Patrick Tan, Atsushi Kaneda
  • Organizer: 15th Asian Epigenomics Meeting
  • Int'l Joint Research
• [Presentation] (イ)Heterochromatin reprogramming and chromatin structural rewiring induced by oncovirus infection in gastric adenocarcinoma (2020)
  • Author(s): (エ)Atsushi Okabe, Kie Kyon Huang, Keisuke Matsusaka, Masaki Fukuyo, Bahityar Rahmutulla, Takayuki Hoshii, Patrick Tan, Atsushi Kaneda
  • Organizer: 第31回日本消化器癌発生学会総会
• [Presentation] Chromatin Structural Aberrations due to oncovirus infection activate neighboring oncogenes through enhancer activation (2020)
  • Author(s): Atsushi Okabe, Kie Kyon Huang, Keisuke Matsusaka, Masaki Fukuyo, Bahityar Rahmutulla, Patrick Tan, Atsushi Kaneda
  • Organizer: 第79回日本癌学会学術総会
  • Invited
• [Presentation] Heterochromatin disruption and chromatin structural rewiring in gastric adenocarcinoma infected by Epstein-Barr virus (2020)
  • Author(s): Atsushi Okabe, Kie Kyon Huang, Keisuke Matsusaka, Masaki Fukuyo, Bahityar Rahmutulla, Patrick Tan, Atsushi Kaneda
  • Organizer: Cold Spring Harbor Meeting Epigenetics and Chromatin
  • Int'l Joint Research