1. ¹Turku Centre for Biotechnology, Turku University and Åbo Akademi University, Turku, Finland
2. ²Biochemistry Department, Institute of Medical Biology, University of Tromsø, Tromsø, Norway
3. ³Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland

Correspondence: Dr PM Jaakkola, Turku Centre for Biotechnology, Tykistökatu 6B, FIN-20520, Turku, Finland. E-mail: panjaa@utu.fi

Received 30 April 2008; Revised 28 August 2008; Accepted 17 September 2008; Published online 20 October 2008.

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.