Analysis of the molecular mechanism of tumorigenesis by abnormal activity of arginine methyltransferase PRMT5

• Project/Area Number: 18K07238
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: University of Miyazaki
• Principal Investigator: Ichikawa Tomonaga 宮崎大学, 医学部, 助教 (80586230)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: PRMT5 / HSP90 / NDRG2 / ATL / がん / synthetic lethality / アルギニンメチル化 / 癌

Outline of Final Research Achievements

We found that the tumor suppressor gene NDRG2 induces the dephosphorylation of various signaling factors through the recruitment of PP2A, resulting in negatively the suppression of the signal transduction pathways. Our previous studies demonstrated that the expression of NDRG2 was significantly down-regulated in many type of tumors, leading to the progression of tumor development through the aberrant activation of the signal transduction pathways. We identified a novel NDRG2/PP2A-binding protein PRMT5 by Comprehensive analysis. The highly phosphorylated PRMT5 in NDRG2 deficient tumor was localized mainly in the cytoplasm, and modulated arginine methylation of cytoplasmic proteins. Therefore, the purpose of this study is to comprehensively analyze the abnormal arginine methylation caused by PRMT5 activity through the decrease of NDRG2 expression, and to elucidate the mechanism of tumorigenesis.

Academic Significance and Societal Importance of the Research Achievements

NDRG2/PP2Aの脱リン酸化基質候補としてアルギニンメチル基酵素群であるPRMT5を新規に同定した。正常細胞ではPRMT5は核に偏在し、ヒストン等をアルギニンメチル化し遺伝子発現制御を行なっている。一方で、NDRG2欠損がんでは細胞質に主に局在し、異なった基質をアルギニンメチル化し腫瘍発症進展に関与している。これらの見地を基盤としたPRMT5機構解析は、NDRG2欠損がん・白血病に選択的に効果のある阻害剤開発に繋がる。さらに、NDRG2は全がんの約42-85%で高頻度に遺伝子発現低下が認められ、適応範囲は非常に広く社会的にも医療的にも貢献ができると考えている。

Research Products

• [Journal Article] Pathophysiological significance of NDRG2 in cancer development through PP2A phosphorylation regulation. (2021)
  • Author(s): Morishita K, Nakahata S, Ichikawa T.
  • Journal Title: Cancer Sci Volume: 112 Issue: 1 Pages: 22-30
  • DOI: 10.1111/cas.14716
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of anti-human CADM1 monoclonal antibodies as a potential therapy for adult T-cell leukemia/lymphoma (2020)
  • Author(s): Chilmi Syahrul、Nakahata Shingo、Fauzi Yanuar Rahmat、Ichikawa Tomonaga、Tani Chikako、Suwanruengsri Mathurot、Yamaguchi Ryoji、Matsuura Tadashi、Kurosawa Gene、Morishita Kazuhiro
  • Journal Title: International Journal of Hematology Volume: 112 Issue: 4 Pages: 496-503
  • DOI: 10.1007/s12185-020-02939-1
  • Peer Reviewed / Open Access
• [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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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
  • 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
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Novel tumor suppressor gene NDRG2 deficiency promotes metabolic disorders and liver cancer development. (2020)
  • Author(s): Tomonaga Ichikawa, Shingo Nakahata, Mitsuru Futakuchi, Ryoji Yamaguchi, Kazuhiro Morishita.
  • Organizer: 第79回日本癌学会
• [Presentation] The activation of protein arginine methyltransferase PRMT5 promotes tumor development through Arginine methylation of HSP90A. (2020)
  • Author(s): Tomonaga Ichikawa, Shingo Nakahata, Masaya Ono, Hidekatsu Iha, and Kazuhiro Morishita.
  • Organizer: 第93回日本生化学会
• [Presentation] PRMT5 inhibition is synthetic lethal with loss of NDRG2 through the suppression of HSP90A in ATL. (2019)
  • Author(s): Tomonaga Ichikawa
  • Organizer: 第81回日本血液学会
• [Presentation] Analysis of the molecular mechanism of metabolism and tumorigenesis through the loss of tumor suppressor gene NDRG2. (2019)
  • Author(s): Tomonaga Ichikawa
  • Organizer: 第78回日本癌学会
• [Presentation] The inhibition of EZH2 suppresses ATL development through the up-regulation of novel tumor suppressor gene NDRG2. (2019)
  • Author(s): Tomonaga Ichikawa
  • Organizer: 第92回日本生化学会
• [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
  • Organizer: 第6回日本HTLV-1学会
• [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構の解析. (2019)
  • Author(s): 市川朝永
  • Organizer: 先端モデル動物支援プラットフォーム「2018年度成果発表会」
• [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
• [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
• [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
• [Presentation] EZH2 overexpression in ATL promotes epigenetic silencing of tumor suppressor gene NDRG2. (2018)
  • Author(s): Tomonaga Ichikawa, Shingo Nakahata, and Kazuhiro Morishita.
  • Organizer: The 9th JSH International Symposium
  • Int'l Joint Research
• [Book] 月刊 細胞 (2021)
  • Author(s): 市川朝永、森下和広
  • Total Pages: 4
  • Publisher: ニューサイエンス社