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.

Download full-text


Available from: Masaaki Komatsu
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatitis C virus (HCV) infection is one of the main causes of chronic liver disease. Viral persistence and pathogenesis rely mainly on the ability of HCV to deregulate specific host processes, including lipid metabolism and innate immunity. Recently, autophagy has emerged as a cellular pathway, playing a role in several aspects of HCV infection. This review summarizes current knowledge on the molecular mechanisms that link the HCV life cycle with autophagy machinery. In particular, we discuss the role of HCV/autophagy interaction in dysregulating inflammation and lipid homeostasis and its potential for translational applications in the treatment of HCV-infected patients.
    Full-text · Article · Aug 2014 · BioMed Research International
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Autoimmune diseases are characterized by the production of antibodies against self-antigens and generally arise from a failure of central or peripheral tolerance. However, these diseases may develop when newly appearing antigens are not recognized as self by the immune system. The mechanism by which some antigens are "invisible" to the immune system is not completely understood. Apoptotic and complement system defects or autophagy imbalance can generate this antigenic autoreactivity. Under particular circumstances, cellular debris containing autoreactive antigens can be recognized by innate immune receptors or other sensors and can eventually lead to autoimmunity. Ubiquitination may be one of the mechanisms protecting autoreactive antigens from the immune system that, if disrupted, can lead to autoimmunity. Ubiquitination is an essential post-translational modification used by cells to target proteins for degradation or to regulate other intracellular processes. The level of ubiquitination is regulated during T cell tolerance and apoptosis and E3 ligases have emerged as a crucial signaling pathway for the regulation of T cell tolerance toward self-antigens. I propose here that an unrecognized role of ubiquitin and ubiquitin-like proteins could be to render intracellular or foreign antigens (present in cellular debris resulting from apoptosis, complement system, or autophagy defects) invisible to the immune system in order to prevent the development of autoimmunity.
    Full-text · Article · Jun 2014 · Frontiers in Immunology
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The role of macroautophagy (hereafter autophagy) in cancer biology and response to clinical intervention is complex. It is clear that autophagy is dysregulated in a wide variety of tumor settings, both during tumor initiation and progression, and in response to therapy. However, the pleiotropic mechanistic roles of autophagy in controlling cell behavior make it difficult to predict in a given tumor setting what the role of autophagy, and, by extension, the therapeutic outcome of targeting autophagy, might be. In this review we summarize the evidence in the literature supporting pro- and anti-tumorigenic and -therapeutic roles of autophagy in cancer. This overview encompasses roles of autophagy in nutrient management, cell death, cell senescence, regulation of proteotoxic stress and cellular homeostasis, regulation of tumor-host interactions and participation in changes in metabolism. We also try to understand, where possible, the mechanistic bases of these roles for autophagy. We specifically expand on the emerging role of genetically-engineered mouse models of cancer in shedding light on these issues in vivo.We also consider how any or all of the above functions of autophagy proteins might be targetable by extant or future classes of pharmacologic agents. We conclude by briefly exploring non-canonical roles for subsets of the key autophagy proteins in cellular processes, and how these might impact upon cancer.
    Full-text · Article · Feb 2014
Show more