Autophagy and metabolic regulation by multiple transcription factors

• Project/Area Number: 26253019
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Niigata University
• Principal Investigator: KOMATSU Masaaki 新潟大学, 医歯学系, 教授 (90356254)
• Co-Investigator(Renkei-kenkyūsha): WAGURI Satoshi 福島県立医科大学, 医学部, 教授 (30244908)
• Research Collaborator: MIZUSHIMA Tsunehiro ; SOGA Tomoyoshi ; OKABE Takayoshi ; NAGANO Tetsuo
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥41,470,000 (Direct Cost: ¥31,900,000、Indirect Cost: ¥9,570,000); Fiscal Year 2016: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000); Fiscal Year 2015: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000); Fiscal Year 2014: ¥25,480,000 (Direct Cost: ¥19,600,000、Indirect Cost: ¥5,880,000)
• Keywords: タンパク質分解 / オートファジー / p62 / Nbr1 / Metabolism / 代謝 / 転写因子 / Nrf2 / PPAR / 糖代謝 / 脂質代謝 / NRF2

Outline of Final Research Achievements

In this research project, we reveal the molecular mechanism of p62/Sqstm1-dependent malignant progression, and suggest that molecular targeting of p62/Sqstm1 represents a potential chemotherapeutic approach against hepatocellular carcinoma (HCC). Phosphorylation of p62/Sqstm1 at Ser349 directs glucose to the glucuronate pathway, and glutamine toward glutathione synthesis through activation of the transcription factor Nrf2. These changes provide HCC cells with tolerance to anti-cancer drugs and proliferation potency. Phosphorylated p62/Sqstm1 accumulates in tumor regions positive for hepatitis C virus (HCV). An inhibitor of phosphorylated p62-dependent Nrf2 activation suppresses the proliferation and anticancer agent tolerance of HCC. Our data indicate that this Nrf2 inhibitor could be used to make cancer cells less resistant to anticancer drugs, especially in HCV-positive HCC patients.

Research Products

• [Int'l Joint Research] Yonsei University(韓国)
• [Int'l Joint Research] ICCNS(China)
• [Int'l Joint Research] University of Kansas Medical Center(米国)
• [Int'l Joint Research] EPFL(Switzerland)
• [Journal Article] Ubiquitylation of p62/sequestosome1 activates its autophagy receptor function and controls selective autophagy upon ubiquitin stress. (2017)
  • Author(s): Peng H, Yang J, Li G, You Q, Han W, Li T, Gao D, Xie X, Lee BH, Du J, Hou J, Zhang T, Rao H, Huang Y, Li Q, Zeng R, Hui L, Wang H, Xia Q, Zhang X, He Y, Komatsu M, Dikic I, Finley D, Hu R.
  • Journal Title: Cell Res. Volume: - Issue: 5 Pages: 657-674
  • DOI: 10.1038/cr.2017.40
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Autophagy in the liver: functions in health and disease. (2017)
  • Author(s): Ueno T, Komatsu M
  • Journal Title: Nat Rev Gastroenterol Hepatol. Volume: 14 Issue: 3 Pages: 170-184
  • DOI: 10.1038/nrgastro.2016.185
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Ezetimibe, an NPC1L1 inhibitor, is a potent Nrf2 activator that protects mice from diet-induced nonalcoholic steatohepatitis. (2016)
  • Author(s): Lee DH, Han DH, Nam KT, Park JS, Kim SH, Lee M, Kim G, Min BS, Cha BS, Lee YS, Sung SH, Jeong H, Ji HW, Lee MJ, Lee JS, Lee HY, Chun Y, Kim J, Komatsu M, Lee YH, Bae SH.
  • Journal Title: Free Radic Biol Med. Volume: 99 Pages: 520-532
  • DOI: 10.1016/j.freeradbiomed.2016.09.009
  • Peer Reviewed / Int'l Joint Research
• [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] Sequestosome 1/p62 Protein Is Associated with Autophagic Removal of Excess Hepatic Endoplasmic Reticulum in Mice. (2016)
  • Author(s): Yang H, Ni HM, Guo F, Ding Y, Shi YH, Lahiri P, Frohlich LF, Rulicke T, Smole C, Schmidt VC, Zatloukal K, Cui Y, Komatsu M, Fan J, Ding WX.
  • Journal Title: J Biol Chem. Volume: 291 Issue: 36 Pages: 18663-18674
  • DOI: 10.1074/jbc.m116.739821
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Megalin-Mediated Tubuloglomerular Alterations in High-Fat Diet-Induced Kidney Disease. (2016)
  • Author(s): Kuwahara S, Hosojima M, Kaneko R, Aoki H, Nakano D, Sasagawa T, Kabasawa H, Kaseda R, Yasukawa R, Ishikawa T, Suzuki A, Sato H, Kageyama S, Tanaka T, Kitamura N, Narita I, Komatsu M, Nishiyama A, Saito A.
  • Journal Title: J Am Soc Nephrol. Volume: -
  • Peer Reviewed
• [Journal Article] Sqstm1-GFP knock-in mice reveal dynamic actions of Sqstm1 during autophagy and under stress conditions in living cells. (2015)
  • Author(s): Atsushi Eino, Shun Kageyama, Takefumi Uemura, Hiromichi Annoh, Tetsuya Saito, Ichiei Narita, Satoshi Waguri, Masaaki Komatsu.
  • Journal Title: Journal of Cell Science Volume: 128 Pages: 4453-4461
  • DOI: 10.1242/jcs.180174
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] p62/SQSTM1 functions as a signaling hub and an autophagy adaptor. (2015)
  • Author(s): Katsuragi Y, Ichimura Y, Komatsu M.
  • Journal Title: FEBS J. Volume: 282 Issue: 24 Pages: 4672-4678
  • DOI: 10.1111/febs.13540
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Proteasome dysfunction activates autophagy and the Keap1-Nrf2 pathway (2014)
  • Author(s): Kageyama S, Sou YS, Uemura T, Kametaka S, Saito T, Ishimura R, Kouno T, Bedford L, Mayer RJ, Lee MS, Yamamoto M, Waguri S, Tanaka K, and Komatsu M.
  • Journal Title: J Biol Chem Volume: 289 Issue: 36 Pages: 24944-24955
  • DOI: 10.1074/jbc.m114.580357
  • Peer Reviewed / Open Access
• [Presentation] オートファジー選択的基質p62/SQSTM1によるがん代謝再編成 (2016)
  • Author(s): 小松雅明
  • Organizer: 日本生化学会 シンポジウム オートファジーのマシナリーと機能
  • Place of Presentation: 仙台国際センター／東北大学川内北キャンパス（宮城県仙台市）
  • Year and Date: 2016-09-24
  • Invited
• [Presentation] Pathophysiological roles of autophagy in mice (2016)
  • Author(s): Komatsu M.
  • Organizer: International Symposium of the Center for Animal Disease Models 2016
  • Place of Presentation: 東京ガーデンパレス（東京都文京区）
  • Year and Date: 2016-07-16
  • Invited
• [Presentation] p62/Sqstm1 regulates glucose and glutamine metabolisms through a transcription-factor NRF2 (2016)
  • Author(s): Komatsu M.
  • Organizer: Keystone Symposium on Autophagy: Molecular and Physiological Mechanism
  • Place of Presentation: ウイスラー（カナダ）
  • Year and Date: 2016-06-05
  • Int'l Joint Research / Invited
• [Presentation] Autophagy defect and tumor development in mouse livers (2016)
  • Author(s): Komatsu M.
  • Organizer: Cold Spring Harbor Asia Ubiquitin Family Autophagy and Diseases
  • Place of Presentation: 蘇州（中国）
  • Year and Date: 2016-04-18
  • Int'l Joint Research / Invited
• [Presentation] Metabolic reprogramming in human hepatocellular carcinoma by p62/SQSTM1 (2016)
  • Author(s): Komatsu M.
  • Organizer: 2016 Minisymposium on Autophagy
  • Place of Presentation: 台北（台湾）
  • Year and Date: 2016-04-15
  • Invited
• [Presentation] Autophagy defect and tumor development in mouse livers (2016)
  • Author(s): Komatsu M.
  • Organizer: APASL STC 2016
  • Place of Presentation: 釜山（韓国）
  • Year and Date: 2016-04-09
  • Int'l Joint Research / Invited
• [Presentation] Metabolic reprogramming in human hepatocellular carcinoma by p62/SQSTM1 (2015)
  • Author(s): 小松雅明
  • Organizer: BMB2015
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市）
  • Year and Date: 2015-11-30
  • Invited
• [Presentation] Metabolic reprogramming in human hepatocellular carcinoma by p62/SQSTM1 (2015)
  • Author(s): Masaaki Komatsu
  • Organizer: merican Association for the study of Liver Diseases (AALD) Basic Science Symposium
  • Place of Presentation: サンフランシスコ（アメリカ）
  • Year and Date: 2015-11-14
  • Int'l Joint Research / Invited
• [Presentation] Metabolic reprogramming in human hepatocellular carcinoma by p62/SQSTM1 (2015)
  • Author(s): Masaaki Komatsu
  • Organizer: The 7th International Symposium on Autophagy 2015
  • Place of Presentation: Smoky Willow, Huangshan, China
  • Year and Date: 2015-03-19 – 2015-03-23
  • Invited
• [Remarks] 「肝臓オートファジーの役割とその異常と肝疾患」に関する包括的な総説を発表しました
  • URL: http://www.niigata-u.ac.jp/news/2017/27691/
• [Remarks] 肝臓がんを抑制する新規化合物を同定しました
  • URL: http://www.niigata-u.ac.jp/news/2016/20330/
• [Remarks] 医歯学系の小松雅明教授がトムソン・ロイターのHCRのCertificateを授与されました
  • URL: http://www.niigata-u.ac.jp/news/2016/16536/
• [Remarks] 新潟大学大学院医師学総合研究科小松研究室
  • URL: http://www.med.niigata-u.ac.jp/bc1/welcome.html
• [Remarks]
  • URL: http://www.med.niigata-u.ac.jp/bc1/welcome.html
• [Remarks] 新潟大学大学院医歯学総合研究科 分子遺伝学講座
  • URL: http://www.med.niigata-u.ac.jp/bc1/welcome.html