Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells

Yoshihiro Inami, Satoshi Waguri, Ayako Sakamoto, Tsuguka Kouno, Kazuto Nakada, Okio Hino, Sumio Watanabe, Jin Ando, Manabu Iwadate, Masayuki Yamamoto, Myung Shik Lee, Keiji Tanaka, Masaaki Komatsu

Research output: Contribution to journalArticlepeer-review

463 Citations (Scopus)


Suppression of autophagy is always accompanied by marked accumulation of p62, a selective autophagy substrate. Because p62 interacts with the Nrf2-binding site on Keap1, which is a Cullin 3-based ubiquitin ligase adapter protein, autophagy deficiency causes competitive inhibition of the Nrf2-Keap1 interaction, resulting in stabilization of Nrf2 followed by transcriptional activation of Nrf2 target genes. Herein, we show that liver-specific autophagy-deficient mice harbor adenomas linked to both the formation of p62- and Keap1-positive cellular aggregates and induction of Nrf2 targets. Importantly, similar aggregates were identified in more than 25% of human hepatocellular carcinomas (HCC), and induction of Nrf2 target genes was recognized in most of these tumors. Gene targeting of p62 in an HCC cell line markedly abrogates the anchorage-independent growth, whereas forced expression of p62, but not a Keap1 interaction-defective mutant, resulted in recovery of the growth defect. These results indicate the involvement of persistent activation of Nrf2 through the accumulation of p62 in hepatoma development.

Original languageEnglish
Pages (from-to)275-284
Number of pages10
JournalJournal of Cell Biology
Issue number2
Publication statusPublished - 2011 Apr 18

ASJC Scopus subject areas

  • Cell Biology


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