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

Author

Listed:
  • Tetsuya Saito

    (Niigata University Graduate School of Medical and Dental Sciences
    Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science)

  • Yoshinobu Ichimura

    (Niigata University Graduate School of Medical and Dental Sciences
    Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science)

  • 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)

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.

Suggested Citation

  • Tetsuya Saito & Yoshinobu Ichimura & Keiko Taguchi & Takafumi Suzuki & Tsunehiro Mizushima & Kenji Takagi & Yuki Hirose & Masayuki Nagahashi & Tetsuro Iso & Toshiaki Fukutomi & Maki Ohishi & Keiko End, 2016. "p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming," Nature Communications, Nature, vol. 7(1), pages 1-16, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12030
    DOI: 10.1038/ncomms12030
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