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p62/Sequestosome 1 regulates transforming growth factor beta signaling and epithelial to mesenchymal transition in

Charles B Trelford1, Evelyn Ng1, Craig I Campbell1

  • 1Schulich School of Medicine and Dentistry, Western University, Department of Physiology and Pharmacology, London, Ontario N6A 5B7, Canada.

Cellular Signalling
|May 17, 2021
PubMed

Insights

The autophagy cargo receptor p62/sequestosome 1 (SQSTM1) influences transforming growth factor beta (TGFβ) receptor trafficking and epithelial to mesenchymal transition (EMT) in lung cancer cells. TGFβ1 reduces p62/SQSTM1, promoting EMT and autophagy.

Area of Science:

  • Cell Biology
  • Cancer Research
  • Molecular Biology

Background:

  • Transforming growth factor beta (TGFβ) signaling pathways are crucial regulators of cellular processes, including epithelial to mesenchymal transition (EMT).
  • EMT is a key event in cancer progression, particularly in non-small cell lung cancer (NSCLC).
  • Autophagy, a cellular degradation process, has emerged as a regulator of EMT.

Purpose of the Study:

  • To investigate the role of the autophagy cargo receptor p62/sequestosome 1 (SQSTM1) in TGFβ receptor trafficking.
  • To determine the impact of p62/SQSTM1 on TGFβ1-induced Smad2 phosphorylation and EMT in A549 NSCLC cells.
  • To elucidate the relationship between TGFβ1 signaling, p62/SQSTM1 levels, and the induction of EMT and autophagy.

Main Methods:

  • Immunofluorescence microscopy to visualize p62/SQSTM1 and TGFβ receptor co-localization.
  • Small interfering RNA (siRNA)-mediated silencing of p62/SQSTM1.
  • Assessment of Smad2 phosphorylation and nuclear translocation.
  • Analysis of EMT markers, actin stress fiber formation, and cell migration.
  • Investigation of proteasomal degradation pathways.

Main Results:

  • p62/SQSTM1 co-localizes with TGFβ receptors in late endosomes.
  • p62/SQSTM1 silencing attenuated Smad2 phosphorylation kinetics but did not affect nuclear translocation.
  • Silencing of p62/SQSTM1 promoted TGFβ1-induced EMT marker expression, actin stress fibers, and cell migration.
  • TGFβ1 signaling, independent of Smad4, decreased p62/SQSTM1 protein levels via proteasomal degradation.
  • p62/SQSTM1 silencing did not inhibit TGFβ1-dependent autophagy.

Conclusions:

  • p62/SQSTM1 plays a role in maintaining the epithelial state of A549 NSCLC cells.
  • TGFβ1 signaling reduces p62/SQSTM1 levels preceding the induction of EMT and autophagy.
  • These findings highlight p62/SQSTM1 as a potential regulator in TGFβ-driven lung cancer progression.
Keywords:
AutophagyEpithelial to mesenchymal transition (EMT)Non-small cell lung cancer (NSCLC)Receptor mediated endocytosisSequestosome 1 (SQSTM1)Transforming growth factor beta (TGFβ)

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