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