Hypoxia-activated autophagy accelerates degradation of SQSTM1/p62

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 hypoxiainducible 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.

Identification of an AAA ATPase VPS4B-Dependent Pathway That Modulates Epidermal Growth Factor Receptor Abundance and Signaling during Hypoxia

“…First, Pa-4 cells were treated with desferrioxamine (DFO), known to induce a hypoxic environment (9,11). Consistent with recent reports by us and others (10,41), sustained hypoxic stress decreased steady-state levels of BECLIN-1 and p62, while the UVRAG level increased during chronic hypoxic exposure (Fig. 1A).…”

“…While hypoxia triggers autophagy (9,10,31,41), little is known about the effect of hypoxia on the stability of key members in autophagy pathway, such as VPS4B, BECLIN-1, p62/SQSTM1 (referred to herein as p62), and UVRAG. We therefore evaluated steady-state protein levels of these molecules under hypoxic stress.…”

“…Results are means and SD from three independent experiments. somal degradation pathway known as autophagy in response to hypoxic stress (31,41). The molecular mechanism by which chronic hypoxia regulates genome-and autophagy-independent adaptive responses via protein degradation is largely unknown.…”

The HIF1α-inducible pro-cell death gene BNIP3 is a novel target of SIM2s repression through cross-talk on the hypoxia response element

“…SIM2s repression of the pro-cell death gene, BNIP3 AL Farrall and ML Whitelaw (Pursiheimo et al, 2009). Reduced protein levels of SQSTM1/p62 were found following prolonged (44 h) treatment of human prostate PC3AR þ cells with hypoxia ( Figure 4eii, compare lanes 1 and 3), and the hypoxia mimetics dimethyloxallyl glycine (DMOG, a hydroxylase inhibitor), consistent with previous reports 6 ± 2.9-fold induction, compared with lane 4 plus SIM2s.myc ¼ 0.96 ± 0.5-fold; average fold change ± s.e.m.…”

Interplay between receptor tyrosine kinases and hypoxia signaling in cancer

“…Hypoxic AKT suppression was associated with a decrease in cell proliferation and induction of autophagy [59], playing an important role in enhancing cell viability in adverse conditions [60,61]. These observations show the plasticity of invasive and proliferative tumor states, which can be mediated by the convergence of hypoxia and MET signaling pathways.…”