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Hypoxia-activated autophagy accelerates degradation of SQSTM1/p62

Oncogene volume 28, pages 334–344 (2009)Cite this article

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.

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Acknowledgements

Taina Kalevo-Mattila is acknowledged for expert technical assistance. The study was supported by The Academy of Finland (grants 200779, 210282 and 8109024), Emil Aaltonen Foundation and Sigrid Juselius Foundation to PMJ, and by grants from the Norwegian Research Council (FUGE) and Norwegian Cancer Society to TJ. PMJ is a research fellow of the Finnish Cancer Institute.

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Authors and Affiliations

  1. Turku Centre for Biotechnology, Turku University and Åbo Akademi University, Turku, Finland

    J-P Pursiheimo, K Rantanen, P T Heikkinen & P M Jaakkola

  2. Biochemistry Department, Institute of Medical Biology, University of Tromsø, Tromsø, Norway

    T Johansen

  3. Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland

    P M Jaakkola

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  1. J-P Pursiheimo
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Correspondence to P M Jaakkola.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Pursiheimo, JP., Rantanen, K., Heikkinen, P. et al. Hypoxia-activated autophagy accelerates degradation of SQSTM1/p62. Oncogene 28, 334–344 (2009). https://doi.org/10.1038/onc.2008.392

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