2. Academic Validation
  3. p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming

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

  • Nat Commun. 2016 Jun 27;7:12030. doi: 10.1038/ncomms12030.
Tetsuya Saito 1 2,  Yoshinobu Ichimura 1 2,  Keiko Taguchi 3,  Takafumi Suzuki 3,  Tsunehiro Mizushima 4,  Kenji Takagi 4,  Yuki Hirose 5,  Masayuki Nagahashi 5,  Tetsuro Iso 3,  Toshiaki Fukutomi 3,  Maki Ohishi 6,  Keiko Endo 6,  Takefumi Uemura 7,  Yasumasa Nishito 8,  Shujiro Okuda 9,  Miki Obata 1,  Tsuguka Kouno 1,  Riyo Imamura 10,  Yukio Tada 10,  Rika Obata 11,  Daisuke Yasuda 11,  Kyoko Takahashi 11,  Tsutomu Fujimura 12,  Jingbo Pi 13,  Myung-Shik Lee 14,  Takashi Ueno 12,  Tomoyuki Ohe 11,  Tadahiko Mashino 11,  Toshifumi Wakai 5,  Hirotatsu Kojima 10,  Takayoshi Okabe 10,  Tetsuo Nagano 10,  Hozumi Motohashi 15,  Satoshi Waguri 7,  Tomoyoshi Soga 6,  Masayuki Yamamoto 3,  Keiji Tanaka 2,  Masaaki Komatsu 1
Affiliations

Affiliations

  • 1 Department of Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
  • 2 Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
  • 3 Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
  • 4 Department of Life Science, Picobiology Institute, Graduate School of Life Science, University of Hyogo, 3-2-1, Hyogo 678-1297, Japan.
  • 5 Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
  • 6 Institute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, Japan.
  • 7 Department of Anatomy and Histology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan.
  • 8 Core Technology and Research Center, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
  • 9 Bioinformatics Laboratory, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
  • 10 The University of Tokyo, Drug Discovery Initiative, University of Tokyo, Tokyo 113-0033, Japan.
  • 11 Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
  • 12 Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
  • 13 Institute for Chemical Safety Sciences, Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709-2137, USA.
  • 14 Severance Biomedical Science Institute and Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea.
  • 15 Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan.
PMID: 27345495 DOI: 10.1038/ncomms12030
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-111126
    98.43%, Keap1/S349-phosphorylated p62 Interaction Inhibitor