p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming

Tetsuya Saito, Yoshinobu Ichimura, Keiko Taguchi, Takafumi Suzuki, Tsunehiro Mizushima, Kenji Takagi, Yuki Hirose, Masayuki Nagahashi, Tetsuro Iso, Toshiaki Fukutomi, Maki Ohishi, Keiko Endo, Takefumi Uemura, Yasumasa Nishito, Shujiro Okuda, Miki Obata, Tsuguka Kouno, Riyo Imamura, Yukio Tada, Rika Obata, Daisuke Yasuda, Kyoko Takahashi, Tsutomu Fujimura, Jingbo Pi, Myung-Shik Lee, Takashi Ueno, Tomoyuki Ohe, Tadahiko Mashino, Toshifumi Wakai, Hirotatsu Kojima, Takayoshi Okabe, Tetsuo Nagano, Hozumi Motohashi, Satoshi Waguri, Tomoyoshi Soga, Masayuki Yamamoto (), Keiji Tanaka () and Masaaki Komatsu ()
Additional contact information
Tetsuya Saito: Niigata University Graduate School of Medical and Dental Sciences
Yoshinobu Ichimura: Niigata University Graduate School of Medical and Dental Sciences
Keiko Taguchi: Tohoku University Graduate School of Medicine
Takafumi Suzuki: Tohoku University Graduate School of Medicine
Tsunehiro Mizushima: Picobiology Institute, Graduate School of Life Science, University of Hyogo, 3-2-1, Hyogo 678-1297, Japan
Kenji Takagi: Picobiology Institute, Graduate School of Life Science, University of Hyogo, 3-2-1, Hyogo 678-1297, Japan
Yuki Hirose: Niigata University Graduate School of Medical and Dental Sciences
Masayuki Nagahashi: Niigata University Graduate School of Medical and Dental Sciences
Tetsuro Iso: Tohoku University Graduate School of Medicine
Toshiaki Fukutomi: Tohoku University Graduate School of Medicine
Maki Ohishi: Institute for Advanced Biosciences, Keio University
Keiko Endo: Institute for Advanced Biosciences, Keio University
Takefumi Uemura: Fukushima Medical University School of Medicine
Yasumasa Nishito: Core Technology and Research Center, Tokyo Metropolitan Institute of Medical Science
Shujiro Okuda: Bioinformatics Laboratory, Niigata University Graduate School of Medical and Dental Sciences
Miki Obata: Niigata University Graduate School of Medical and Dental Sciences
Tsuguka Kouno: Niigata University Graduate School of Medical and Dental Sciences
Riyo Imamura: The University of Tokyo, Drug Discovery Initiative, University of Tokyo
Yukio Tada: The University of Tokyo, Drug Discovery Initiative, University of Tokyo
Rika Obata: Faculty of Pharmacy, Keio University
Daisuke Yasuda: Faculty of Pharmacy, Keio University
Kyoko Takahashi: Faculty of Pharmacy, Keio University
Tsutomu Fujimura: Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine
Jingbo Pi: Institute for Chemical Safety Sciences, Hamner Institutes for Health Sciences, Research Triangle Park
Myung-Shik Lee: Yonsei University College of Medicine
Takashi Ueno: Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine
Tomoyuki Ohe: Faculty of Pharmacy, Keio University
Tadahiko Mashino: Faculty of Pharmacy, Keio University
Toshifumi Wakai: Niigata University Graduate School of Medical and Dental Sciences
Hirotatsu Kojima: The University of Tokyo, Drug Discovery Initiative, University of Tokyo
Takayoshi Okabe: The University of Tokyo, Drug Discovery Initiative, University of Tokyo
Tetsuo Nagano: The University of Tokyo, Drug Discovery Initiative, University of Tokyo
Hozumi Motohashi: Institute of Development, Aging and Cancer, Tohoku University
Satoshi Waguri: Fukushima Medical University School of Medicine
Tomoyoshi Soga: Institute for Advanced Biosciences, Keio University
Masayuki Yamamoto: Tohoku University Graduate School of Medicine
Keiji Tanaka: Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science
Masaaki Komatsu: Niigata University Graduate School of Medical and Dental Sciences

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12030

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