title: p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming.
abstract: p62/Sqstm1 is a multifunctional protein involved in cell survival, growth and death, that is degraded by autophagy. Amplification of the p62/Sqstm1 gene, and aberrant accumulation and phosphorylation of p62/Sqstm1, have been implicated in tumour development. Herein, 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 towards 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 tumour 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.
authors.affiliation: Department of Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.|Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.|Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Ichimura
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Taguchi
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Life Science, Picobiology Institute, Graduate School of Life Science, University of Hyogo, 3-2-1, Hyogo 678-1297, Japan.
authors.forename: Tsunehiro
authors.initials: T
authors.lastname: Mizushima
authors.affiliation: Department of Life Science, Picobiology Institute, Graduate School of Life Science, University of Hyogo, 3-2-1, Hyogo 678-1297, Japan.
authors.forename: Kenji
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authors.lastname: Takagi
authors.affiliation: Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hirose
authors.affiliation: Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nagahashi
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Iso
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Fukutomi
authors.affiliation: Institute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Ohishi
authors.affiliation: Institute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Endo
authors.affiliation: Department of Anatomy and Histology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan.
authors.forename: Takefumi
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authors.lastname: Uemura
authors.affiliation: Core Technology and Research Center, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Nishito
authors.affiliation: Bioinformatics Laboratory, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
authors.forename: Shujiro
authors.initials: S
authors.lastname: Okuda
authors.affiliation: Department of Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Obata
authors.affiliation: Department of Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
authors.forename: Tsuguka
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authors.lastname: Kouno
authors.affiliation: The University of Tokyo, Drug Discovery Initiative, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Riyo
authors.initials: R
authors.lastname: Imamura
authors.affiliation: The University of Tokyo, Drug Discovery Initiative, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Tada
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Obata
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yasuda
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Fujimura
authors.affiliation: Institute for Chemical Safety Sciences, Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709-2137, USA.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Pi
authors.affiliation: Severance Biomedical Science Institute and Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Myung-Shik
authors.identifier: 0000-0003-3292-1720
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ueno
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ohe
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
authors.forename: Tadahiko
authors.initials: T
authors.lastname: Mashino
authors.affiliation: Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Wakai
authors.affiliation: The University of Tokyo, Drug Discovery Initiative, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Hirotatsu
authors.initials: H
authors.lastname: Kojima
authors.affiliation: The University of Tokyo, Drug Discovery Initiative, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Okabe
authors.affiliation: The University of Tokyo, Drug Discovery Initiative, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nagano
authors.affiliation: Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan.
authors.forename: Hozumi
authors.initials: H
authors.lastname: Motohashi
authors.affiliation: Department of Anatomy and Histology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Waguri
authors.affiliation: Institute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, Japan.
authors.forename: Tomoyoshi
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authors.lastname: Soga
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
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mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016174:Hepacivirus / Q000302:isolation & purification*; D006526:Hepatitis C / Q000150:complications* / Q000821:virology; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000821:virology; D051379:Mice; D046228:Microarray Analysis; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D000071456:Sequestosome-1 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein