Synergistic action of master transcription factors controls epithelial-to-mesenchymal transition

Autor: Liwen Zhang, Haiyue Liu, Mengzhu Xue, Chang Hongyuan, Peng Wang, Yuwei Liu, Shaowei Du
Rok vydání: 2016
Předmět:
0301 basic medicine
BRD4
Epithelial-Mesenchymal Transition
Lung Neoplasms
JUNB
Adenocarcinoma of Lung
Antineoplastic Agents
Cell Cycle Proteins
Biology
Adenocarcinoma
Proto-Oncogene Protein c-ets-2
Histones
03 medical and health sciences
Transforming Growth Factor beta
Cell Line
Tumor
Genetics
Humans
Epithelial–mesenchymal transition
Smad3 Protein
RNA
Small Interfering
Transcription factor
Regulation of gene expression
Sequence Analysis
RNA
Gene Expression Profiling
Nuclear Proteins
Computational Biology
Epithelial Cells
Transforming growth factor beta
Azepines
Triazoles
Phenotype
Survival Analysis
Cell biology
Gene expression profiling
Gene Expression Regulation
Neoplastic
030104 developmental biology
Hepatocyte Nuclear Factor 4
embryonic structures
Cancer research
biology.protein
Transcriptome
Signal Transduction
Transcription Factors
Zdroj: Nucleic Acids Research
ISSN: 1362-4962
Popis: Epithelial-to-mesenchymal transition (EMT) is a complex multistep process in which phenotype switches are mediated by a network of transcription factors (TFs). Systematic characterization of all dynamic TFs controlling EMT state transitions, especially for the intermediate partial-EMT state, represents a highly relevant yet largely unexplored task. Here, we performed a computational analysis that integrated time-course EMT transcriptomic data with public cistromic data and identified three synergistic master TFs (ETS2, HNF4A and JUNB) that regulate the transition through the partial-EMT state. Overexpression of these regulators predicted a poor clinical outcome, and their elimination readily abolished TGF-β-induced EMT. Importantly, these factors utilized a clique motif, physically interact and their cumulative binding generally characterized EMT-associated genes. Furthermore, analyses of H3K27ac ChIP-seq data revealed that ETS2, HNF4A and JUNB are associated with super-enhancers and the administration of BRD4 inhibitor readily abolished TGF-β-induced EMT. These findings have implications for systematic discovery of master EMT regulators and super-enhancers as novel targets for controlling metastasis.
Databáze: OpenAIRE
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