p62/Sequestosome 1 regulates transforming growth factor beta signaling and epithelial to mesenchymal transition in A549 cells |
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Affiliation: | 1. Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates;2. Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates;3. Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates;4. Department of Pathology, School of Medicine, University of Michigan, Ann Arbor, MI, USA;1. Department of Rehabilitation Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China;2. Department of Rehabilitation Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, PR China |
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Abstract: | Transforming growth factor beta (TGFβ) receptor trafficking regulates many TGFβ-dependent cellular outcomes including epithelial to mesenchymal transition (EMT). EMT in A549 non-small cell lung cancer (NSCLC) cells has recently been linked to the regulation of cellular autophagy. Here, we investigated the role of the autophagy cargo receptor, p62/sequestosome 1 (SQSTM1), in regulating TGFβ receptor trafficking, TGFβ1-dependent Smad2 phosphorylation and EMT in A549 NSCLC cells. Using immunofluorescence microscopy, p62/SQSTM1 was observed to co-localize with TGFβ receptors in the late endosome. Small interfering RNA (SiRNA)-mediated silencing of p62/SQSTM1 resulted in an attenuated time-course of Smad2 phosphorylation but did not alter Smad2 nuclear translocation. However, p62/SQSTM1 silencing promoted TGFβ1-dependent EMT marker expression, actin stress fiber formation and A549 cell migration. We further observed that Smad4-independent TGFβ1 signaling decreased p62/SQSTM1 protein levels via a proteasome-dependent mechanism. Although p62/SQSTM1 silencing did not impede TGFβ-dependent autophagy, our results suggest that p62/SQSTM1 may aid in maintaining A549 cells in an epithelial state and TGFβ1 decreases p62/SQSTM1 prior to inducing EMT and autophagy. |
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