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Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells

Yoshihiro Inami1, Satoshi Waguri, Ayako Sakamoto

  • 1Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8501, Japan.

The Journal of Cell Biology
|April 13, 2011
PubMed

Insights

Autophagy suppression leads to p62 accumulation, activating Nrf2 and promoting liver cancer (hepatocellular carcinoma). Targeting p62 inhibits tumor growth, highlighting its role in hepatoma development.

Area of Science:

  • Cell Biology
  • Oncology
  • Molecular Biology

Background:

  • Autophagy suppression causes p62 accumulation, which competitively inhibits the Nrf2-Keap1 interaction.
  • This inhibition stabilizes Nrf2, leading to the transcriptional activation of Nrf2 target genes.

Purpose of the Study:

  • To investigate the role of p62 accumulation and Nrf2 activation in liver cancer development.
  • To determine the therapeutic potential of targeting p62 in hepatocellular carcinoma (HCC).

Main Methods:

  • Utilized liver-specific autophagy-deficient mice to study hepatoma development.
  • Analyzed human HCC tissues for p62 and Keap1-positive aggregates and Nrf2 target gene induction.
  • Employed gene targeting and forced expression of p62 in an HCC cell line.

Main Results:

  • Autophagy-deficient mice developed adenomas with p62/Keap1 aggregates and Nrf2 target gene induction.
  • Similar aggregates and Nrf2 activation were found in over 25% of human HCCs.
  • p62 gene targeting abrogated HCC cell growth, while p62 overexpression restored it.

Conclusions:

  • Persistent Nrf2 activation due to p62 accumulation is implicated in hepatoma development.
  • p62 is a potential therapeutic target for hepatocellular carcinoma.

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