Therapeutic strategy to target epithelial stem cell specific epigenetic regulation

• Project/Area Number: 17K16332
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Dermatology
• Research Institution: Kanazawa University
• Principal Investigator: hazawa masaharu 金沢大学, 新学術創成研究機構, 助教 (40622460)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2019: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 核膜孔複合体 / エピジェネティクス / 腫瘍生物学 / 分子細胞生物学 / 扁平上皮癌 / 遺伝子発現 / 上皮分化 / 皮膚組織幹細胞 / 癌 / 遺伝子 / ゲノム / 細胞・組織

Outline of Final Research Achievements

This study aims to unmask stem-cell specific epigenetics regulation by nuclear pore complex (NPC).
I found that NPCs-mediated spatial-regulation of genomic DNA resulted in activation of oncogene-expression. Further, interacting mode between NPC and transcription environment was identified. These results gives annotation spatio-temporal information of transcription regulators and its target genes. Further study of NPC-mediated genomic structure and function will unmask how NPC regulates cell-fate determination mechanisms and cancer initiation-/progression.

Academic Significance and Societal Importance of the Research Achievements

遺伝子発現制御は細胞の形質決定に関わる機構である。これまでに幹細胞や癌細胞で中心的役割を担う転写制御因子とこれらの標的遺伝子の解明がなされてきたが、核内における構造・機能相関の解明は未だなされていかった。
本研究により、NPCが核内ゲノムの配置・機能制御に関与すること、さらにNPCとゲノムの相互作用機序の一部を解明できた。本研究により明らかにされた、NPC-ゲノム相互作用阻害により、人為的な遺伝子発現操作をできる可能性があり、再生医療や癌治療への応用が期待される。

Research Products

• [Int'l Joint Research] Cedars-Sinai Medical Center(米国)
• [Int'l Joint Research] National University of Singapore(シンガポール)
• [Journal Article] Nucleoporin TPR (translocated promoter region, nuclear basket protein) upregulation alters MTOR-HSF1 trails and suppresses autophagy induction in ependymoma. (2020)
  • Author(s): Dewi FRP, Jiapaer S, Kobayashi A, Hazawa M, Ikliptikawati DK, Hartono, Sabit H, Nakada M, Wong RW.
  • Journal Title: Autophagy Volume: 24 Pages: 1-12
  • Peer Reviewed / Open Access
• [Journal Article] Karyopherin-β1 Regulates Radioresistance and Radiation-Increased Programmed Death-Ligand 1 Expression in Human Head and Neck Squamous Cell Carcinoma Cell Lines (2020)
  • Author(s): Hazawa M, Yoshino H, Nakagawa Y, Shimizume R, Nitta K, Sato Y, Sato M, Wong RW, Kashiwakura I
  • Journal Title: Cancers Volume: 12(4) Issue: 4 Pages: 908-908
  • DOI: 10.3390/cancers12040908
  • Peer Reviewed / Open Access
• [Journal Article] Disease-specific alteration of karyopherin-α subtype establishes feed-forward oncogenic signaling in head and neck squamous cell carcinoma (2019)
  • Author(s): Hazawa Masaharu、Sakai Kie、Kobayashi Akiko、Yoshino Hironori、Iga Yoshihiro、Iwashima Yuki、Lim Kee Sing、Chih-Cheng Voon Dominic、Jiang Yan-Yi、Horike Shin-ichi、Lin De-Chen、Wong Richard W.
  • Journal Title: Oncogene Volume: 39 Issue: 10 Pages: 2212-2223
  • DOI: 10.1038/s41388-019-1137-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Direct Visualization of Avian Influenza H5N1 Hemagglutinin Precursor and its Conformational Change by High-Speed Atomic Force Microscopy (2019)
  • Author(s): Lim SK, Mohamed MS, Wang H, Hartono, Hazawa M, Kobayashi A, Voon DC, Kodera N, Ando T and Wong RW
  • Journal Title: BBA - General Subjects Volume: 印刷中 Issue: 2 Pages: 129313-129313
  • DOI: 10.1016/j.bbagen.2019.02.015
  • Peer Reviewed / Open Access
• [Journal Article] Novel function of HATs and HDACs in homologous recombination through acetylation of human RAD52 at double-strand break sites (2018)
  • Author(s): Yasuda Takeshi、Kagawa Wataru、Tajima Katsushi
  • Journal Title: PLOS Genetics Volume: 14 Issue: 3 Pages: 1007277-1007277
  • DOI: 10.1371/journal.pgen.1007277
  • NAID: 120006459820
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Co-activation of super-enhancer-driven CCAT1 by TP63 and SOX2 promotes squamous cancer progression. (2018)
  • Author(s): Jiang Y, Jiang YY, Xie JJ, Mayakonda A, Hazawa M, Chen L, Xiao JF, Li CQ, Huang ML, Ding LW, Sun QY, Xu L, Kanojia D, Jeitany M, Deng JW, Liao LD, Soukiasian HJ, Berman BP, Hao JJ, Xu LY, Li EM, Wang MR, Bi XG, Lin DC, Koeffler HP.
  • Journal Title: Nat Commun. Volume: 9 Issue: 1 Pages: 3619-3619
  • DOI: 10.1038/s41467-018-06081-9
  • Peer Reviewed / Open Access
• [Journal Article] Colorectal cancer cells require glycogen synthase kinase-3β for sustaining mitosis via translocated promoter region (TPR)-dynein interaction (2018)
  • Author(s): Dewi Firli R.P.、Domoto Takahiro、Hazawa Masaharu、Kobayashi Akiko、Douwaki Takayuki、Minamoto Toshinari、Wong Richard W.
  • Journal Title: Oncotarget Volume: 9 Issue: 17 Pages: 13337-52
  • DOI: 10.18632/oncotarget.24344
  • NAID: 120006452368
  • Peer Reviewed / Open Access
• [Journal Article] Rock-dependent phosphorylation of NUP62 regulates p63 nuclear transport and cell fate of squamous cell carcinoma. (2018)
  • Author(s): Hazawa M, Lin D, Kobayashi A, Jiang YY, Dewi FRP, Mohamed MS, Hartono H, Nakada S, Meguro-Horike M, Horike S, Koeffler H and Wong RW
  • Journal Title: EMBO Rep. Volume: 19 Issue: 1 Pages: 73-88
  • DOI: 10.15252/embr.201744523
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High-Speed Atomic Force Microscopy Reveals Loss of Nuclear Pore Resilience as a Dying Code in Colorectal Cancer Cells. (2017)
  • Author(s): Mohamed MS, Kobayashi A, Taoka A, Watanabe-Nakayama T, Kikuchi Y, Hazawa M, Minamoto T, Fukumori Y, Kodera N, Uchihashi T, Ando T, Wong RW
  • Journal Title: ACS Nano. Volume: 11(6) Issue: 6 Pages: 5567-5578
  • DOI: 10.1021/acsnano.7b00906
  • Peer Reviewed / Open Access
• [Presentation] Disease-specific alteration of karyopherin-alpha subtypes establishes feedforward oncogenic signaling in squamous cell carcinoma (2018)
  • Author(s): Hazawa M, Sakai K, Kobayashi A, Wong RW.
  • Organizer: The 2018 ASCB | EMBO Meeting
  • Int'l Joint Research
• [Presentation] DNA損傷応答における核膜孔複合体の役割. (2018)
  • Author(s): 伊賀 祥紘、羽澤 勝治、Richard Wong
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] Nuclear transport system caused by disease-specific Karyopherin alternation (2018)
  • Author(s): K. Sakai, M. Hazawa, A. Kobayashi, RW. Wong
  • Organizer: Joint Annual Meeting of 70th JSCB and 51st JSDB
• [Presentation] ROCK-dependent phosphorylation of NUP62 regulates p63 nuclear transport in squamous cell carcinoma. (2017)
  • Author(s): Hazawa M, Kobayashi A, Wong RW
  • Organizer: The 2017 ASCB | EMBO Meeting
  • Int'l Joint Research
• [Presentation] 皮膚組織幹細胞におけるNup153 の役割 (2017)
  • Author(s): 塚原涼太，小林亜紀子，Wong RW，羽澤勝治
  • Organizer: 第69回細胞生物学会大会
• [Book] NPCs in Mitosis and Chromosome Segregation In book: Nuclear Pore Complexes in Genome Organization, Function and Maintenance, chap 10 (2018)
  • Author(s): Hazawa M, Kobayashi A, and Wong RW
  • Total Pages: 240
  • Publisher: Springer
  • ISBN: 9783319716145