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Dysregulation of stress signaling leading to oncogenesis by NDRG2-deficicency

Research Project

Project/Area Number 17H03581
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Tumor biology
Research InstitutionUniversity of Miyazaki

Principal Investigator

Morishita Kazuhiro  宮崎大学, 医学部, 教授 (80260321)

Co-Investigator(Kenkyū-buntansha) 尾野 雅哉  国立研究開発法人国立がん研究センター, 研究所, 研究員 (00270900)
中畑 新吾  宮崎大学, 医学部, 准教授 (80437938)
市川 朝永  宮崎大学, 医学部, 助教 (80586230)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000)
Fiscal Year 2019: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2017: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000)
KeywordsATL / HTLV-1 / NDRG2 / PRMT5 / HSP90 / アルギニンメチル化 / PP2A / sythethic lethality / HTLV1 / client protein / 癌 / 感染症
Outline of Final Research Achievements

We have identified a novel PTEN-binding NDRG2 tumor suppressor gene from the genome analysis of adult T-cell leukemia Isolated as a protein and used for the regulation of PTEN activity by PP2A-mediated dephosphorylation of PTEN NDRG2 has been implicated in the pathogenesis of multiple cancers and has been shown to play a key role in the development of new HSP 90/PRMT5 complex. In particular, down-regulation of PRMT5 expression caused HSP90 dysfunction in ATL/cancer cells and reduced AKT The degradation and apoptosis of many Client proteins, including NDRG2 Therefore, NDRG2-deficient cancer cells show abnormalities in phosphorylation and arginine methylation, and cancer cells It is suggested that this is associated with a specific increase in HSP90 activity.

Academic Significance and Societal Importance of the Research Achievements

この研究ではNDRG2癌抑制遺伝子機能異常を中心に研究を行っており、NDRG2異常をきたす癌・白血病におけるタンパク質リン酸化、メチル化修飾異常を網羅的に明らかしている。、その中心として新たながん細胞特異的HSP90の新規活性調節機構としてPRMT5によるアルギニンメチル化を同定した。この発癌機構を基礎とした新規治療薬の開発へつながる重要な研究である。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (42 results)

All 2020 2019 2018 2017

All Journal Article (10 results) (of which Int'l Joint Research: 8 results,  Peer Reviewed: 10 results,  Open Access: 10 results) Presentation (32 results) (of which Int'l Joint Research: 7 results,  Invited: 2 results)

  • [Journal Article] Clinical significance of soluble CADM1 as a novel marker for adult T-cell leukemia/lymphoma.2020

    • Author(s)
      Nakahata S, Syahrul C, Nakatake A, Sakamoto K, Yoshihama M, Nishikata I, Ukai Y, Matsuura T, Kameda T, Shide K, Kubuki Y, Hidaka T, Kitanaka A, Ito A, Takemoto S, Nakano N, Saito M, Iwanaga M, Sagara Y, Mochida K, Amano M, Maeda K, Sueoka E, Okayama A, Utsunomiya A, Shimoda K, Watanabe T, Morishita K.
    • Journal Title

      Haematologica

      Volume: 105 Issue: 2 Pages: 1-1

    • DOI

      10.3324/haematol.2019.234096

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Novel PRMT5-mediated arginine methylations of HSP90A are essential for maintenance of HSP90A function in NDRG2low ATL and various cancer cells.2020

    • Author(s)
      Ichikawa T, Shanab O, Nakahata S, Shimosaki S, Manachai N, Ono M, Iha H, Shimoda K, Morishita K
    • Journal Title

      Biochim Biophys Acta Mol Cell Res

      Volume: 1867 Issue: 2 Pages: 118615-118615

    • DOI

      10.1016/j.bbamcr.2019.118615

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The regulation of NDRG2 expression during ATLL development after HTLV-1 infection.2019

    • Author(s)
      Ichikawa T, Nakahata S, Fujii M, Iha H, Shimoda K, Morishita K.
    • Journal Title

      Biochim Biophys Acta Mol Basis Dis

      Volume: 1865 Issue: 10 Pages: 2633-2646

    • DOI

      10.1016/j.bbadis.2019.07.001

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The expression of cell adhesion molecule 1 and its splicing variants in S?zary cells and cell lines from cutaneous T‐cell lymphoma2019

    • Author(s)
      Yamaguchi Mari、Morizane Shin、Hamada Toshihisa、Miyake Tomoko、Sugaya Makoto、Iwata Hiroaki、Fujii Kazuyasu、Haramoto‐Shiratsuki Rie、Nakagawa Yuki、Miura Mayumi、Ohshima Koichi、Morishita Kazuhiro、Takahashi Takahide、Imada Masahide、Okada Ken、Uehara Jiro、Sowa‐Osako Junko、Iwatsuki Keiji
    • Journal Title

      The Journal of Dermatology

      Volume: 46 Issue: 11 Pages: 967-977

    • DOI

      10.1111/1346-8138.15078

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Degradation of p47 by autophagy contributes to CADM1 overexpression in ATLL cells through the activation of NF-κB.2019

    • Author(s)
      Sarkar B, Nishikata I, Nakahata S, Ichikawa T, Shiraga T, Saha HR, Fujii M, Tanaka Y, Shimoda K, Morishita K.
    • Journal Title

      Sci Rep

      Volume: 9 Issue: 1 Pages: 3491-3491

    • DOI

      10.1038/s41598-019-39424-7

    • NAID

      120006825908

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] CGRP-CRLR/RAMP1 signal is important for stress-induced hematopoiesis.2019

    • Author(s)
      Suekane A, Saito Y, Nakahata S, Ichikawa T, Ogoh H, Tsujikawa K, Morishita K.
    • Journal Title

      Sci Rep

      Volume: 9 Issue: 1 Pages: 429-429

    • DOI

      10.1038/s41598-018-36796-0

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Overexpression of absent in melanoma 2 in oral squamous cell carcinoma contributes to tumor progression.2019

    • Author(s)
      Nakamura Y, Nakahata S, Kondo Y, Izumi A, Yamamoto K, Ichikawa T, Tamura T, Noumi K, Yamashita Y, Morishita K.
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 509 Issue: 1 Pages: 82-82

    • DOI

      10.1016/j.bbrc.2018.12.066

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Suppression of GPR56 expression by pyrrole-imidazole polyamide represents a novel therapeutic drug for AML with high EVI1 expression2018

    • Author(s)
      Saha Hasi Rani、Kaneda-Nakashima Kazuko、Shimosaki Shunsuke、Suekane Akira、Sarkar Bidhan、Saito Yusuke、Ogoh Honami、Nakahata Shingo、Inoue Kentaro、Watanabe Takayoshi、Nagase Hiroki、Morishita Kazuhiro
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 1-12

    • DOI

      10.1038/s41598-018-32205-8

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Direct-Injection Electron Ionization-Mass Spectrometry Metabolomics Method for Analyzing Blueberry Leaf Metabolites That Inhibit Adult T-cell Leukemia Proliferation2018

    • Author(s)
      Kai Hisahiro、Uesawa Yoshihiro、Kunitake Hisato、Morishita Kazuhiro、Okada Yoshihito、Matsuno Koji
    • Journal Title

      Planta Medica

      Volume: 85 Issue: 01 Pages: 81-87

    • DOI

      10.1055/a-0725-8295

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] BCL11B is frequently downregulated in HTLV-1-infected T-cells through Tax-mediated proteasomal degradation2017

    • Author(s)
      Permatasari H., Nakahata S., Ichikawa T., Morishita K.
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 490 Issue: 3 Pages: 1086-1092

    • DOI

      10.1016/j.bbrc.2017.06.172

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Anti-transferrin receptor1(TFR1)antibody is a promising drug candidate for the treatment of adult T-cell leukemia/lymphoma2019

    • Author(s)
      Shingo Nakahata, Shunsuke Shimosaki, Tomonaga Ichikawa, Takuro Kameda, Tomonori Hidaka, Yoko Kubuki, Gene Kurosawa, Kazuya Shimoda, Kazuhiro Morishita
    • Organizer
      19th INTERNATIONAL CONFERENCE ON HUMAN RETROVIROLOGY
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Toward the practical application of novel diagnostic tests and development of early detection markers for Adult T-Cell Leaukemia/Lymphoma in HTLV-1-carriers by host-parasite interaction in peru2019

    • Author(s)
      Shingo Nakahata, Eiji Nagayasu, Kazuhiro Morishita, Hruhiko Maruyama, Yutaka Suzuki, Masao Iwanaga, Yuetsu Tanaka, Martin Montes, Eduardo Gotuzzo
    • Organizer
      19th INTERNATIONAL CONFERENCE ON HUMAN RETROVIROLOGY
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Cell adhesion molecule 1 (CADM1) is an attractive target for the diagnosis and treatment of adult T-cell leukemia/lymphoma.2019

    • Author(s)
      Tomonaga Ichikawa, Ayako Nakatake, Bidhan Sarker, Shingo Nakahata, Kuniyo Sakamoto, Shunsuke Shimosaki, Ichiro Nishikata, Toshiyuki Shiraga, Kazuhiro Morishita
    • Organizer
      19th INTERNATIONAL CONFERENCE ON HUMAN RETROVIROLOGY
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ATLにおけるCADM1発現の機能とその臨床的意義2019

    • Author(s)
      中畑新吾、Chilmi Syahrul、Yanuar Fauzi、市川朝永、森下和広
    • Organizer
      第6回日本HTLV-1学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] ATLLにおける可溶性CADM1の産生機序2019

    • Author(s)
      吉浜麻生、中畑新吾、市川朝永、森下和広
    • Organizer
      第6回日本HTLV-1学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] がん抑制遺伝子NDRG2発現低下によるJak/STAT情報伝達系活性化機構2019

    • Author(s)
      市川朝永、中畑新吾、尾野雅哉、中武彩子、阪本訓代、森下和広
    • Organizer
      第6回日本HTLV-1学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] The inhibition of EZH2 suppresses ATL development through the up-regulation of novel tumor suppressor gene2019

    • Author(s)
      Tomonaga Ichikawa, Shingo Nakahata, Kazuhiro Morishita.
    • Organizer
      第92回日本生化学会.
    • Related Report
      2019 Annual Research Report
  • [Presentation] ATLにおける可溶型CADM1の産生亢進機構2019

    • Author(s)
      吉浜麻生, 中畑新吾, 市川朝永, 森下和広
    • Organizer
      第78回日本癌学会.
    • Related Report
      2019 Annual Research Report
  • [Presentation] Analysis of the molecular mechanism of metabolism and tumorigenesis through the loss of tumor suppressor gene NDRG22019

    • Author(s)
      Tomonaga Ichikawa, Shingo Nakahata, Mitsuru Futakuchi, Kazuhiro Morishita.
    • Organizer
      第78回日本癌学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Development of a therapeutic antibody targeting CADM1 for the treatment of ATLL2019

    • Author(s)
      Syahrul Chilmi、中畑新吾、市川朝永、松浦正、黒澤仁、森下和広
    • Organizer
      第81回日本血液学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] PRMT5 inhibition is synthetic lethal with loss of NDRG2 through the suppression of HSP90A in ATL2019

    • Author(s)
      Tomonaga Ichikawa, Obeid Shanab, Shingo Nakahata, Masaya Ono, Hidekatsu Iha, and Kazuhiro Morishita.
    • Organizer
      第81回日本血液学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Down-regulation of p47 induces high expression of CADM1 via the NF-κB pathway in adult T-cell leukemia/lymphoma2019

    • Author(s)
      中畑新吾、Bidhan Sarkar、西片 一郎、市川 朝永、藤井 雅寛、伊波 英克、森下 和広
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 成人T細胞白血病/リンパ腫(ATLL)の発症機構2018

    • Author(s)
      森下和広
    • Organizer
      日本人類遺伝学会主催 第25回臨床採苗遺伝学セミナー
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] HTLV-1 infection in Peru and Japan2018

    • Author(s)
      森下和広、中畑新吾、長安英治、丸山治彦、鈴木穣、岩永正子、田中勇悦、Martin Montes、Eduardo Gotuzzo
    • Organizer
      第18回日秘国際医学シンポジウム
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] EZH2 overexpression in ATL promotes epigenetic silencing of tumor suppressor gene NDRG22018

    • Author(s)
      Tomonaga Ichikawa, Shingo Nakahata, and Kazuhiro Morishita.
    • Organizer
      The 9th JSH International Symposium.
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Identification of novel antisense RNAs in the genome of bovine leukemia virus (BLV).2018

    • Author(s)
      Shingo Nakahata, Chikako Tani, Tomonaga Ichikawa, Hirohisa Mekata, Kazuhiro Morishita
    • Organizer
      第30回世界牛病学会
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] トランスフェリン受容体抗体はモガムリズマブ治療難治性のATLLの増殖抑制に有効である.2018

    • Author(s)
      中畑新吾、下崎俊介、市川朝永、亀田拓郎、日高智徳、久冨木庸子、黒澤仁、下田和哉、森下和広.
    • Organizer
      第5回日本HTLV-1学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] アルギニンメチル化転移酵素PRMT5異常活性によるATL発症機構の解析.2018

    • Author(s)
      市川朝永、Obeid Shanab、中畑新吾、尾野雅哉、伊波英克、中武彩子、阪本訓代、森下和広
    • Organizer
      第5回日本HTLV-1学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Short-form of BCL11B contributes to tumorigenesis of adult T-cell leukemia/lymphoma.2018

    • Author(s)
      Happy Kurnia Permatasari, Shingo Nakahata, Tomonaga Ichikawa, Kotaro Shide, Takuro Kameda, Kazuya Shimoda, Masaya Ono, Kazuhiro Morishita.
    • Organizer
      第5回日本HTLV-1学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ATLにおけるオートファジーによるNF-κB負の制御因子p47の不活化は、NF-κBシグナルを増強しCADM1高発現をもたらす.2018

    • Author(s)
      中畑新吾、Bidhan Sarkar、西片一郎、市川朝永、藤井雅寛、井上純一郎、伊波英克、下田和哉、森下和広.
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Arginine methylation of HSP90A by protein arginine methyltransferase PRMT5 promotes development of adult T-cell leukemia.2018

    • Author(s)
      Tomonaga Ichikawa, Obeid Shanab, Shingo Nakahata, Masaya Ono, Hidekatsu Iha, and Kazuhiro Morishita.
    • Organizer
      第77回日本癌学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] High efficacy of anti-TFR1 antibody against the growth of mogamulizmab-resistant ATLL cells2018

    • Author(s)
      Shingo Nakahata, Shunsuke Shimosaki, Tomonaga Ichikawa, Takuro Kameda, Tomonori Hidaka, Yoko Kubuki, Gene Kurosawa, Kazuya Shimoda, Kazuhiro Morishita.
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Overexpression of EZH2 confers ATL development through the suppression of tumor suppressor gene NDRG2.2018

    • Author(s)
      Tomonaga Ichikawa, Shingo Nakahata, Kazuhiro Morishita.
    • Organizer
      第80回日本血液学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 新規がん抑制遺伝子NDRG2欠損マウスにおける脂質代謝異常および腫瘍形成機能の解析2018

    • Author(s)
      市川朝永、中畑新吾、山口良二、二口充、森下和広
    • Organizer
      先端モデル動物支援プラットフォーム
    • Related Report
      2018 Annual Research Report
  • [Presentation] Maintenance of HSP90A by PRMT5 arginine methylation by NDRG2-deficient ATLL and other cancers2018

    • Author(s)
      Kazuhiro Morishita1 , Tomonaga Ichikawa1 , Shingo Nakahata1 , Masaya Ono
    • Organizer
      11th AACR-JCA Joint Conference
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Down-regulation of p47 induces high expression of CADM1 via the NF-kB pathway in adult T-cell leukemia2017

    • Author(s)
      Bidhan Sarkar, 西片一朗, 中畑新吾, 市川朝永, 藤井雅寛, 伊波英克, 森下和広
    • Organizer
      平成29年度日本生化学会九州支部例会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Short-from of BCL11B contributes to tumorigenesis of adult T-cell leukemia2017

    • Author(s)
      Happy Permatasari, 中畑新吾, 市川朝永, 齋藤祐介, 滝智彦, 谷脇雅史, 森下和広
    • Organizer
      平成29年度日本生化学会九州支部例会
    • Related Report
      2017 Annual Research Report
  • [Presentation] アルギニンメチル化によるHSP90A活性調節機構の解析2017

    • Author(s)
      市川朝永, Obeid Shanab, 中畑新吾, 伊波英克, 尾野雅哉, 中武彩子, 阪本訓代, 森下和広
    • Organizer
      平成29年度日本生化学会九州支部例会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 成人T細胞白血病(ATL)に対するアルギニンメチル化転移酵素PRMT5阻害による抗腫瘍効果の検討2017

    • Author(s)
      市川朝永、Obeid Shanab、中畑新吾、伊波英克、尾野雅哉、中武彩子、阪本訓代、森下和広
    • Organizer
      第4回日本HTLV-1学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] ATLにおけるNDRG2発現低下は細胞ストレス応答異常に関与する2017

    • Author(s)
      中畑新吾、市川朝永、斎藤祐介、滝智彦、谷脇雅史、森下和広
    • Organizer
      第4回日本HTLV-1学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Synthetic lethality of PRMT5 inhibition in NDRG2-deficient adult T-cell leukemia through HSP90A dysfunction2017

    • Author(s)
      Tomonaga Ichikawa, Obeid Shanab, Shingo Nakahata, Shunsuke Shimosaki, Nawin Manachai, Hidekatsu Iha, Kazuya Shimoda, Masaya Ono, Mohammed N. Ismail, Ahmed Y. Nassar and Kazuhiro Morishita. 
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 新規がん抑制遺伝子NDRG2によるがん進展および転移の分子機構の解明2017

    • Author(s)
      市川朝永、田村知丈、中畑新吾、二口充、森下和広.
    • Organizer
      第76回日本癌学会
    • Related Report
      2017 Annual Research Report

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Published: 2017-04-28   Modified: 2021-02-19  

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