HDAC1-Smad3-mSin3A complex is required for Smad3-induced transcriptional inhibition of hepatocyte growth factor receptor in human lung cancers
| Autor: | Ze-Ping Yang, Ying Liu, Tian-Rui Xu, Xi Mu, Yu-Ting Shao, Hao-Xin Gui, Hong Zeng, Lu-Yao Chen, Yang Yang, Xiao-Xi Guo, Qian Hao, Su An, Jun Peng |
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| Rok vydání: | 2020 |
| Předmět: |
Transcriptional Activation
Vascular Endothelial Growth Factor A Cancer Research Low protein Epithelial-Mesenchymal Transition Lung Neoplasms Histone Deacetylase 1 Phosphatidylinositol 3-Kinases Cell Line Tumor Transcriptional regulation Gene silencing Humans Smad3 Protein Promoter Regions Genetic PI3K/AKT/mTOR pathway beta Catenin Gene knockdown integumentary system Chemistry Connective Tissue Growth Factor General Medicine Proto-Oncogene Proteins c-met Cell biology CTGF Gene Expression Regulation Neoplastic Sin3 Histone Deacetylase and Corepressor Complex Hepatocyte Growth Factor Receptor Cyclooxygenase 2 biological phenomena cell phenomena and immunity Chromatin immunoprecipitation |
| Zdroj: | Carcinogenesis. 42(4) |
| ISSN: | 1460-2180 |
| Popis: | c-Met hyperactivity has been observed in numerous neoplasms. Several researchers have shown that the abnormal activation of c-Met is mainly caused by transcriptional activation. However, the molecular mechanism behind this transcriptional regulation is poorly understood. Here, we suggest that Smad3 negatively regulates the expression and activation of c-Met via a transcriptional mechanism. We explore the molecular mechanisms that underlie Smad3-induced c-Met transcription inhibition. We found in contrast to the high expression of c-Met, Smad3 showed low protein and mRNA levels. Smad3 and c-Met expressions were inconsistent between lung cancer tissues and cell lines. We also found that Smad3 overexpression suppresses whereas Smad3 knockdown significantly promotes Epithelial-Mesenchymal Transition and production of the angiogenic factors VEGF, CTGF and COX-2 through the ERK1/2 pathway. In addition, Smad3 overexpression decreases whereas Smad3 knockdown significantly increases protein and mRNA levels of invasion-related β-catenin and FAK through the PI3K/Akt pathway. Furthermore, using the chromatin immunoprecipitation analysis method, we demonstrate that a transcriptional regulatory complex consisting of HDAC1, Smad3 and mSin3A binds to the promoter of the c-Met gene. By either silencing endogenous mSin3A expression with siRNA or by pretreating cells with a specific HDAC1 inhibitor (MS-275), Smad3-induced transcriptional suppression of c-Met could be effectively attenuated. These results demonstrate that Smad3-induced inhibition of c-Met transcription depends on of a functional transcriptional regulatory complex that includes Smad3, mSin3A and HDAC1 at the c-Met promoter. Collectively, our findings reveal a new regulatory mechanism of c-Met signaling, and suggest a potential molecular target for the development of anticancer drugs. |
| Databáze: | OpenAIRE |
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