Epigenetic regulation of Smad2 and Smad3 by profilin-2 promotes lung cancer growth and metastasis

Nat Commun. 2015 Sep 10:6:8230. doi: 10.1038/ncomms9230.

Abstract

Altered transforming growth factor-β (TGF-β) signalling has been implicated in tumour development and progression. However, the molecular mechanism behind this alteration is poorly understood. Here we show that profilin-2 (Pfn2) increases Smad2 and Smad3 expression via an epigenetic mechanism, and that profilin-2 and Smad expression correlate with an unfavourable prognosis of lung cancer patients. Profilin-2 overexpression promotes, whereas profilin-2 knockdown drastically reduces, lung cancer growth and metastasis. We show that profilin-2 suppresses the recruitment of HDAC1 to Smad2 and Smad3 promoters by preventing nuclear translocation of HDAC1 through protein-protein interaction at the C terminus of both proteins, leading to the transcriptional activation of Smad2 and Smad3. Increased Smad2 and Smad3 expression enhances TGF-β1-induced EMT and production of the angiogenic factors VEGF and CTGF. These findings reveal a new regulatory mechanism of TGF-β1/Smad signalling, and suggest a potential molecular target for the development of anticancer drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Connective Tissue Growth Factor / metabolism
  • Epigenesis, Genetic
  • Epithelial-Mesenchymal Transition*
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Neoplastic*
  • HEK293 Cells
  • Histone Deacetylase 1 / metabolism*
  • Humans
  • Immunohistochemistry
  • Immunoprecipitation
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Nude
  • Microscopy, Confocal
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Profilins / genetics*
  • Promoter Regions, Genetic
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction
  • Smad2 Protein / genetics*
  • Smad2 Protein / metabolism
  • Smad3 Protein / genetics*
  • Smad3 Protein / metabolism
  • Transforming Growth Factor beta1 / metabolism*
  • Tumor Burden
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • CCN2 protein, human
  • PFN2 protein, human
  • Profilins
  • SMAD2 protein, human
  • SMAD3 protein, human
  • Smad2 Protein
  • Smad3 Protein
  • TGFB1 protein, human
  • Transforming Growth Factor beta1
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Connective Tissue Growth Factor
  • HDAC1 protein, human
  • Histone Deacetylase 1