Enhancement of sensitivity to anti-cancer immunity in NRF2-addiected cancers

• Project/Area Number: 16K15228
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Tohoku University
• Principal Investigator: Motohashi Hozumi 東北大学, 加齢医学研究所, 教授 (00282351)
• Project Period (FY): 2016-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2016: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
• Keywords: 転写因子 / がん / がん遺伝子 / 酸化ストレス応答 / KEAP1 / NRF2 / がん細胞 / がん微小環境 / 乳がん / ストレス

Outline of Final Research Achievements

NRF2 is a master transcriptional activator playing a critical role in the defense mechanism against oxidative insults. NRF2 activates genes encoding cytoprotective enzymes and antioxidant proteins in response to electrophiles and reactive oxygen species (ROS), conferring resistance against xenobiotic and oxidative stress. While NRF2 activation is beneficial to our health, NRF2 is responsible for the malignant progression of various human cancers. To develop a new anti-cancer therapy for NRF2-addicted malignant cancers, we examined molecular mechanisms how NRF2 activation influences on the cancer evasion from the anti-cancer immunity. We found that NRF2 in cancer cells reduces expression of MHC class I and other genes involved in the antigen presentation, suggesting that NRF2 promotes the cancer evasion from the anti-cancer immunity.

Research Products

• [Journal Article] Glucocorticoid receptor signaling represses the antioxidant response by inhibiting histone acetylation mediated by the transcriptional activatpr NRF2 (2017)
  • Author(s): Alam MM, Okazaki K, Nguyen LTT, Ota N, Kitamura H, Murakami S, Shima H, Igarashi K, Sekine H, Motohashi H
  • Journal Title: J Biol Chem Volume: 印刷中 Issue: 18 Pages: 7519-7530
  • DOI: 10.1074/jbc.m116.773960
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. (2016)
  • Author(s): Kobayashi EH, Suzuki T, Funayama R, Nagashima T, Hayashi M, Sekine H, Tanaka N, Moriguchi T, Motohashi H, Nakayama K, Yamamoto M.
  • Journal Title: Nat Commun Volume: 7 Issue: 1 Pages: 11624-11624
  • DOI: 10.1038/ncomms11624
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming (2016)
  • Author(s): Saito T, Ichimura Y, Taguchi K, Suzuki T, Mizushima T, Takagi K, Hirose Y, Nagahashi M, Iso T, Fukutomi T, Ohishi M, Endo K, Uemura T, Nishito Y, Okuda S, Obata M, Kouno T, Imamura R, Tada Y, Obata R, Yasuda D, Takahashi K, Fujimura T, Pi J, Lee MS, Ueno T, Ohe T, Mashino T, Wakai T, Kojima H, Okabe T, Nagano T et al.
  • Journal Title: Nature Commun Volume: 7 Issue: 1 Pages: 12030-12030
  • DOI: 10.1038/ncomms12030
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD271 regulates the proliferation and motility of hypopharyngeal cancer cells (2016)
  • Author(s): Mochizuki M, Tamai K, Imai T, Sugawara S, Ogama N, Nakamura M, Matsuura K, Yamaguchi K, Satoh K, Sato I, Motohashi H, Sugamura K, Tanaka N
  • Journal Title: Sci Reｐ Volume: 6 Issue: 1 Pages: 30707-30707
  • DOI: 10.1038/srep30707
  • Peer Reviewed / Open Access
• [Journal Article] The structural origin of metabolic quantitative diversity. (2016)
  • Author(s): Koshiba S, Motoike I, Kojima K, Hasegawa T, Shirota M, Saito T, Saigusa D, Danjoh I, Katsuoka F, Ogishima S, ... Yamamoto M.
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 31463-31463
  • DOI: 10.1038/srep31463
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of Protocols for Global Metabolomics by LC-MS for Biomarker Discovery. (2016)
  • Author(s): Saigusa D, Okamura Y, Motoike IN, Katoh Y, Kurosawa Y, Saijyo R, Koshiba S, Yasuda J, Motohashi H, Sugawara J, Tanabe O, Kinoshita K, Yamamoto M
  • Journal Title: PLoS One Volume: 11 Issue: 8 Pages: e0160555-e0160555
  • DOI: 10.1371/journal.pone.0160555
  • Peer Reviewed / Open Access
• [Journal Article] Protein polysulfidation-dependent persulfide dioxygenase activity of ethylmalonic encephalopathy protein 1 (2016)
  • Author(s): Jung M, Kasamatsu S, Matsunaga T, Akashi S, Ono K, Nishimura A, Morita M, Abdul Hamid H, Fujii S, Kitamura H, Sawa T, Ida T, Motohashi H, Akaike T.
  • Journal Title: Biochem Biophys Res Commun Volume: 480 Issue: 2 Pages: 180-186
  • DOI: 10.1016/j.bbrc.2016.10.022
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Redox signaling regulated by electrophiles and reactive sulfur species (2016)
  • Author(s): Nishida M, Kumagai Y, Ihara H, Fujii S, Motohashi H, Akaike T.
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 58 Issue: 2 Pages: 91-98
  • DOI: 10.3164/jcbn.15-111
  • NAID: 130005132519
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Redox signaling regulated by an electrophilic cyclic nucleotide and reactive cysteine persulfides (2016)
  • Author(s): Fujii S, Sawa T, Nishida M, Ihara H, Ida T, Motohashi H, Akaike T.
  • Journal Title: Arch Biochem Biophys. Volume: 595 Pages: 140-146
  • DOI: 10.1016/j.abb.2015.11.008
  • Peer Reviewed / Open Access
• [Journal Article] 酸化ストレス応答転写因子NRF2の転写制御機構 (2016)
  • Author(s): 関根弘樹、本橋ほづみ
  • Journal Title: 実験医学 Volume: 34 Pages: 2517-2524
  • Peer Reviewed
• [Journal Article] Recent advances in elucidating KEAP1-NRF2 functions in hematopoietic/immune cells and leukemic cells (2016)
  • Author(s): Murakami S, Motohashi H
  • Journal Title: Rinsho Ketsueki Volume: 57 Pages: 1860-1868
  • NAID: 130005420735
  • Peer Reviewed
• [Presentation] 8-ニトロcGMPとタンパク質poly-S-グアニル化による親電子シグナルの可逆制御 (2017)
  • Author(s): 赤司壮一郎、笠松真吾、ジョン ミンギョン、松永哲郎、井田智章、藤井重元、澤 智裕、熊谷嘉人、本橋ほづみ、赤池孝章
  • Organizer: 第90回日本細菌学会総会
  • Place of Presentation: 仙台国際センター（仙台）
  • Year and Date: 2017-03-19
• [Presentation] アルコールデヒドロゲナーゼ５タンパク質ポリスフリド化の酵素活性制御機能 (2017)
  • Author(s): Chazia Glulamo Abdula、笠松真吾、西村明、Md. Morshedul Alam、井田智章、松永哲郎、藤井重元、居原 秀、本橋ほづみ、赤池孝章
  • Organizer: 第90回日本細菌学会総会
  • Place of Presentation: 仙台国際センター（仙台）
  • Year and Date: 2017-03-19
• [Presentation] 細菌のイオウ呼吸はすべての生物種に保存されている：哺乳類における新しいエネルギー代謝経路・イオウ呼吸の発見 (2017)
  • Author(s): 赤池孝章、井田智章、松永哲郎、守田匡伸、笠松真吾、西村 明、藤井重元、居原 秀、ジョン ミンギョン、 赤司壮一郎、澤 智裕、本橋ほづみ
  • Organizer: 第90回日本細菌学会総会
  • Place of Presentation: 仙台国際センター（仙台）
  • Year and Date: 2017-03-19
• [Presentation] 有機水銀定量曝露による細胞内システインパースルフィドの分解消耗と親電子シグナルの破綻 (2017)
  • Author(s): 井田智章、笠松真吾、居原秀、ヒシャム アブドル ハミル、チャジア グラモ アブドドゥラ、津々木博康、澤智裕、熊谷嘉人、本橋ほづみ、西田基宏、赤池孝章
  • Organizer: 第16回分子予防環境医学研究会
  • Place of Presentation: 熊本市国際交流会館（熊本）
  • Year and Date: 2017-02-03
• [Presentation] KEAP1-NRF2 system in stress responss and cancer malignancy (2017)
  • Author(s): 本橋ほづみ
  • Organizer: Kumamoto University Advence Research Project A & Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers, International Symposium
  • Place of Presentation: Kumamoto University, Kumamoto
  • Int'l Joint Research / Invited
• [Presentation] KEAP1-NRF2 system in anti-oxidant response and regulation of cell proliferation and senescence (2017)
  • Author(s): 本橋ほづみ
  • Organizer: International Symposium “Redox Signaling in host defense and oxidative stress” 第90回日本細菌学会総会
  • Place of Presentation: 仙台国際センター（仙台）
  • Int'l Joint Research / Invited
• [Presentation] Systemic activation of NRF2 alleviates chronic inflammation in a mouse model of lethal autoimmune diseases (2016)
  • Author(s): 鈴木琢磨、村上昌平、張替秀郎、本橋ほづみ
  • Organizer: 第45回日本免疫学会学術集会
  • Place of Presentation: 沖縄コンベンションセンター（沖縄）
  • Year and Date: 2016-12-05
• [Presentation] KEAP1-NRF2 system as a cysteine-based redox sensor-effector for our defense mechanism (2016)
  • Author(s): 本橋ほづみ
  • Organizer: Lecture series
  • Place of Presentation: The Jagiellonian University, Krakow, Polamd
  • Year and Date: 2016-11-21
  • Invited
• [Presentation] NRF2の活性化がもたらす自己免疫疾患の慢性炎症改善作用 (2016)
  • Author(s): 鈴木琢磨、村上昌平、山本雅之、張替秀郎、本橋ほづみ
  • Organizer: 第89回日本生化学会大会合同大会
  • Place of Presentation: 仙台国際センター（仙台）
  • Year and Date: 2016-09-25
• [Presentation] がん細胞におけるNRF2依存性転写活性化機構のゲノムワイドな解析 (2016)
  • Author(s): 岡崎慶斗、関根弘樹、勝岡史城、植野和子、長﨑正朗、山本雅之、本橋ほづみ
  • Organizer: 第89回日本生化学会大会合同大会
  • Place of Presentation: 仙台国際センター（仙台）
  • Year and Date: 2016-09-25
• [Presentation] 転写因子NRF1のOGT-HCF-1複合体を介した分解制御機構 (2016)
  • Author(s): 関根弘樹、加藤幸一郎、福田愛菜、鈴木教郎、辻田忠志、岡崎慶斗、Md. Morshedul Alam、小林聡、山本雅之、本橋ほづみ
  • Organizer: 第89回日本生化学会大会合同大会
  • Place of Presentation: 仙台国際センター（仙台）
  • Year and Date: 2016-09-25
• [Presentation] 2-ヒドロキシグルタル酸の精子形成・胎児発生における生理的役割の検討 (2016)
  • Author(s): 百々美奈、北村大志、太田奈緒、三枝大輔、勝岡史城、千葉初音、岡江寛明、有馬隆博、小関健由、本橋ほづみ
  • Organizer: 第89回日本生化学会大会合同大会
  • Place of Presentation: 仙台国際センター（仙台）
  • Year and Date: 2016-09-25
• [Presentation] KEAP1の体細胞変異がもたらす腫瘍形成能促進機構の解明 (2016)
  • Author(s): 北村大志、小野寺好明、鈴木貴、本橋ほづみ
  • Organizer: 第89回日本生化学会大会合同大会
  • Place of Presentation: 仙台国際センター（仙台）
  • Year and Date: 2016-09-25
• [Presentation] 造血幹細胞におけるKEAP1-NRF2制御系の機能解析 (2016)
  • Author(s): 村上昌平、山本雅之、本橋ほづみ
  • Organizer: 第89回日本生化学会大会合同大会
  • Place of Presentation: 仙台国際センター（仙台）
  • Year and Date: 2016-09-25
• [Presentation] 精巣における2-ヒドロキシグルタル酸の産生機構と生理的作用の検討 (2016)
  • Author(s): 百々美奈、北村大志、太田奈緒、三枝大輔、小関健由、本橋ほづみ
  • Organizer: 日本生化学会東北支部会 第82会例会
  • Place of Presentation: 弘前大学医学部 基礎大講堂（弘前）
  • Year and Date: 2016-05-21
• [Presentation] KEAP1の体細胞変異はRASシグナルと協調して腫瘍形成能を促進させる (2016)
  • Author(s): 北村大志、本橋ほづみ
  • Organizer: 日本生化学会東北支部会 第82会例会
  • Place of Presentation: 弘前大学医学部 基礎大講堂（弘前）
  • Year and Date: 2016-05-21
• [Presentation] 致死的自己免疫疾患に対してNRF2の恒常的活性化がもたらす抗炎症作用の解析 (2016)
  • Author(s): 鈴木琢磨、村上昌平、山本雅之、張替秀郎、本橋ほづみ
  • Organizer: 日本生化学会東北支部会 第82会例会
  • Place of Presentation: 弘前大学医学部 基礎大講堂（弘前）
  • Year and Date: 2016-05-21
• [Presentation] Translation-coupled protein polysulfation, a unique biosynthesis pathway of cysteine persulfide (2016)
  • Author(s): Ida T, Ihara H, Wei F, Tomizawa K, Kasamatsu S, Matsunaga T, Kumagai Y, Sawa T, Motohashi H, Akaike T
  • Organizer: The 9th International Conference of the Biology, Chemistry and Theapeutic applications of nitric oxide
  • Place of Presentation: Sendai International Center (Sendai)
  • Year and Date: 2016-05-20
  • Int'l Joint Research
• [Presentation] Regulatory mechanisms of alcohol dehydrogenase 5 activity via protein polysulfuration (2016)
  • Author(s): Kasamatsu S, Md. Morshedul Alam, Ida T, Matsunaga T, Fujii S, Ihara H, Motohashi H, Akaike T
  • Organizer: The 9th International Conference of the Biology, Chemistry and Theapeutic applications of nitric oxide
  • Place of Presentation: Sendai International Center (Sendai)
  • Year and Date: 2016-05-20
  • Int'l Joint Research
• [Presentation] Regulation of reactive sulfuer species by ethylmalonic encephalopathy protein 1, persulfide dioxygenase (2016)
  • Author(s): Jung S, Matsuaga T, Kitamura H, Ono K, Ida T, Fujii S, Sawa T, Motohashi H, Akaike T
  • Organizer: The 9th International Conference of the Biology, Chemistry and Theapeutic applications of nitric oxide
  • Place of Presentation: Sendai International Center (Sendai)
  • Year and Date: 2016-05-20
  • Int'l Joint Research
• [Presentation] Regulation of mitochondrial energy metabolism by cysteine persulfide produced by mitochondrial cysteinyl-tRNA synthass (2016)
  • Author(s): Sato F, Okutomi M Matsunaga T, Kasamatsu S, Kaneki M, Ida T, Morita M, Tomizawa K, Fujii S, Motohashi H, Akaiake T
  • Organizer: The 9th International Conference of the Biology, Chemistry and Theapeutic applications of nitric oxide
  • Place of Presentation: Sendai International Center (Sendai)
  • Year and Date: 2016-05-20
  • Int'l Joint Research
• [Presentation] Regulation of mitochondria biogenesis by cysteine persulfide produced by cysteinyl-tRNA synthetase (2016)
  • Author(s): Nishimura A, Matsunaga T, Ida T, Kasamatsu S, Morita M, Fanyan W, Tomizawa K, Fujii S, Motohashi H, Akaike T
  • Organizer: The 9th International Conference of the Biology, Chemistry and Theapeutic applications of nitric oxide
  • Place of Presentation: Sendai International Center (Sendai)
  • Year and Date: 2016-05-20
  • Int'l Joint Research
• [Presentation] NRF2活性化による強大音曝露に伴う酸化ストレスからの内耳保護効果（１） -Nrf2-/-マウス解析- (2016)
  • Author(s): 本蔵陽平、水足邦雄、塩谷彰浩、川瀬哲明、香取幸夫、本橋ほづみ
  • Organizer: 第117回日本耳鼻咽喉科学会通常総会・学術講演会
  • Place of Presentation: 名古屋国際会議場（名古屋）
  • Year and Date: 2016-05-18
• [Presentation] NRF2依存性環境ストレス応答：内耳酸化ストレス障害の軽減に対するNRF2の貢献 (2016)
  • Author(s): 本橋ほづみ
  • Organizer: 第49回日本毒性学会学術年会 シンポジウム
  • Place of Presentation: ウインクあいち（愛知県産業労働センター）（名古屋）
  • Invited
• [Presentation] がんの悪性化と酸化ストレス応答機構 (2016)
  • Author(s): 本橋ほづみ
  • Organizer: 安田女子大学・薬学部・薬学科 10周年記念学術講演会
  • Place of Presentation: 安田女子大学（広島）
  • Invited
• [Presentation] KEAP1-NRF2制御系による酸化ストレス応答と細胞老化制御 (2016)
  • Author(s): 本橋ほづみ
  • Organizer: 第69回日本酸化ストレス学会学術集会 教育講演
  • Place of Presentation: 仙台国際センター（仙台）
  • Invited
• [Presentation] Purification and analysis of endogenous NRF2 complex in the presence and absence of active PI3K-AKT signaling (2016)
  • Author(s): 本橋ほづみ
  • Organizer: 第89回日本生化学会大会 シンポジウム「細胞のロバストネスを規定するタンパク質複合体のダイナミクス」
  • Place of Presentation: 仙台国際センター（仙台）
  • Invited
• [Presentation] Enhancement mechanisms of NRF2-dependent transcriptional activation in cancer cells がん細胞におけるNRF2依存的転写活性の増強メカニズム (2016)
  • Author(s): 本橋ほづみ
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Invited
• [Presentation] 造血細胞の分化・増殖における酸化ストレス応答機構の役割 (2016)
  • Author(s): 本橋ほづみ
  • Organizer: 第78回日本血液学会学術集会 教育講演
  • Place of Presentation: パシフィコ横浜（横浜）
  • Invited
• [Presentation] NRF2の活性制御による加齢疾患の予防と治療の可能性 (2016)
  • Author(s): 本橋ほづみ
  • Organizer: スマート・エイジングカレッジin東京
  • Place of Presentation: 東京丸の内・東北大学東京分室（東京）
  • Invited
• [Presentation] KEAP1-NRF2制御系による酸化ストレス応答とその破綻 (2016)
  • Author(s): 本橋ほづみ
  • Organizer: Marianna Research Council (MRC)
  • Place of Presentation: 聖マリアンナ医科大学（川崎）
  • Invited
• [Presentation] Nrf2活性化によるNrf2依存性がんの治療戦略 (2016)
  • Author(s): 本橋ほづみ
  • Organizer: 日本放射線影響学会 第59回大会
  • Place of Presentation: JMSアステールプラザ（広島）
  • Invited
• [Presentation] NRF2による酸化ストレス応答と細胞老化制御 (2016)
  • Author(s): 本橋ほづみ
  • Organizer: 第11回臨床ストレス応答学会大会 シンポジウム
  • Place of Presentation: 山口大学医学部（宇部）
  • Invited
• [Presentation] Antioxidant response and cell senescence regulation by KEAP1-NRF2 system (2016)
  • Author(s): 本橋ほづみ
  • Organizer: “Frontiers in aging research toward healthy longevity”
  • Place of Presentation: 丸の内MY PLAZAホール（東京）
  • Invited
• [Presentation] KEAP1-NRF2 system in stress response and cancer malignancy (2016)
  • Author(s): 本橋ほづみ
  • Organizer: III International Scienctific Conference: Oxygen 2016
  • Place of Presentation: The Jagiellonian University, Krakow, Poland
  • Int'l Joint Research / Invited
• [Presentation] 酸化ストレス応答機構KEAP1-NRF2経路による細胞老化制御 (2016)
  • Author(s): 本橋ほづみ
  • Organizer: 第39回日本分子生物学会年会 シンポジウム「エピゲノム制御：疾患発症における意義」
  • Place of Presentation: パシフィコ横浜（横浜）
  • Invited
• [Presentation] NRF2 and ROS metabolism. Educational session (2016)
  • Author(s): 本橋ほづみ
  • Organizer: Educational session. ESMO Asia 2016
  • Place of Presentation: Suntec Signapore Convention & Exhibition Centre, Singapore
  • Int'l Joint Research / Invited