Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells

Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8501, Japan.
The Journal of Cell Biology (Impact Factor: 9.83). 04/2011; 193(2):275-84. DOI: 10.1083/jcb.201102031
Source: PubMed


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.

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Available from: Masaaki Komatsu,
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    • "In agreement with this observation, hepatocyte-specific atg7 knockout mice show liver damage associated with increases in hepatic TGs and cholesterol [111, 116]. Notably, in these mice, accumulation of p62 accelerates liver damage, which leads to the development of hepatic cancer via persistent activation of the Nrf2 pathway [117–119]. "
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    • "The sequential recruitment of DUB enzymes may negatively regulate the autophagy process. The physiological relevance of the cargo receptors is underscored by the presence of mutations in p62 and optineurin genes found in human patients with Paget’s disease of bone, primary open angle glaucoma, amyotrophic lateral sclerosis, or hepatocellular carcinoma (77–82). "
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    • "It is also noteworthy that several cancer cell lines where autophagy loss has been shown to be synthetic lethal with activation of the KRAS pathway, such as A549 and NCI-H23, also bear mutant alleles of KEAP1 that, in any case, result in constitutive activation of NRF2 signaling, regardless of autophagy status (Shibata et al., 2008). In other instances, the loss of autophagy proteins such as ATG7 and ATG5 may predispose to tumorigenesis without additional oncogenes, for example in the liver, and in this scenario failure to degrade p62 is implicated (Inami et al., 2011; Takamura et al., 2011). Deregulated NRF2 signaling is seen here and it is possible that, in this context, elevated NRF2 signaling might promote the cancer. "

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