p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming PMID: 27345495

ADC Targets in Oncology

2026-04-10

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

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.

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.