Hypoxia-activated autophagy accelerates degradation of SQSTM1/p62

Oncogene. 2009 Jan 22;28(3):334-44. doi: 10.1038/onc.2008.392. Epub 2008 Oct 20.

Abstract

Sequestosome 1 (SQSTM1/p62) is a multifunctional protein involved in signal transduction, protein degradation and cell transformation. Hypoxia is a common feature of solid tumours that promotes cancer progression. Here, we report that p62 is downregulated in hypoxia in carcinoma cells and that the expression is rapidly restored in response to reoxygenation. The hypoxic p62 downregulation did not occur at the mRNA level and was independent of the hypoxic signal mediators hypoxia-inducible factor (HIF) and von Hippel-Lindau tumour suppressor protein as well as the activity of HIF-prolyl hydroxylases and was not mediated by proteosomal destruction. Autophagy was activated in hypoxia and was required for p62 degradation. The hypoxic degradation of p62 was blocked by autophagy inhibitors as well as by the attenuation of Atg8/LC3 expression. Downregulation of p62 was required for hypoxic extracellular regulated kinase (ERK)-1/2 phosphorylation. Attenuation of p62 in normoxia activated and forced expression of p62 in hypoxia blocked the activation of ERK-1/2. The results demonstrate that hypoxic activation of autophagy induces clearance of p62 protein and implies a role for p62 in the regulation of hypoxic cancer cell survival responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Autophagy*
  • Blotting, Western
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Enzyme Inhibitors / pharmacology
  • HeLa Cells
  • Head and Neck Neoplasms / metabolism
  • Head and Neck Neoplasms / pathology
  • Humans
  • Hypoxia / metabolism*
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Keratinocytes / cytology
  • Keratinocytes / metabolism
  • Kidney / cytology
  • Kidney / metabolism
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Osteosarcoma / metabolism
  • Osteosarcoma / pathology
  • Oxygen / metabolism*
  • Phosphorylation
  • Procollagen-Proline Dioxygenase / antagonists & inhibitors
  • Procollagen-Proline Dioxygenase / genetics
  • Procollagen-Proline Dioxygenase / metabolism
  • RNA, Small Interfering / pharmacology
  • Sequestosome-1 Protein
  • Von Hippel-Lindau Tumor Suppressor Protein / antagonists & inhibitors
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Enzyme Inhibitors
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Small Interfering
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Procollagen-Proline Dioxygenase
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • VHL protein, human
  • Oxygen