Epigenetic regulation of Smad2 and Smad3 by profilin-2 promotes lung cancer growth and metastasis.
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.
State Key Laboratory of Cell Biology, Innovation Center for Cell Signalling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Yun-Neng
YN
Tang
State Key Laboratory of Cell Biology, Innovation Center for Cell Signalling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Wei-Qiao
WQ
Ding
State Key Laboratory of Cell Biology, Innovation Center for Cell Signalling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Xiao-Jie
XJ
Guo
State Key Laboratory of Cell Biology, Innovation Center for Cell Signalling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Xin-Wang
XW
Yuan
State Key Laboratory of Cell Biology, Innovation Center for Cell Signalling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Dong-Mei
DM
Wang
State Key Laboratory of Cell Biology, Innovation Center for Cell Signalling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Jian-Guo
JG
Song
D000818:Animals; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D051304:Profilins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics* / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D047368:Tumor Burden; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C526317:CCN2 protein, human; C495741:PFN2 protein, human; D051304:Profilins; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D055513:Connective Tissue Growth Factor; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1