Regulatory crosstalk between lineage-survival oncogenesKLF5, GATA4andGATA6cooperatively promotes gastric cancer development
| Autor: | Willie Yu, Angie Lay Keng Tan, Patrick Tan, Xin Xiu Sam, Niantao Deng, Jeanie Wu, Wei Keat Wan, Steve Rozen, Na-Yu Chia, Su-Ting Tay, Yansong Zhu, Wai-Keong Wong, Anna Gan, Kakoli Das, Lourdes Trinidad M Dominguez, Gek San Tan, Minghui Lee, Khee Chee Soo, Longyu Hu, Bin Tean Teh, Kiat Hon Lim, Huck-Hui Ng, Dachuan Huang, Liang Kee Goh |
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| Rok vydání: | 2014 |
| Předmět: |
endocrine system
Kruppel-Like Transcription Factors Mice Nude Biology Transcriptome Stomach Neoplasms GATA6 Transcription Factor Gene expression Tumor Cells Cultured Animals Humans Genetic Predisposition to Disease Gene Silencing Promoter Regions Genetic Gene Transcription factor Cell Proliferation GATA6 GATA4 Gene Expression Profiling Gastroenterology Promoter Oncogenes GATA4 Transcription Factor Gene Expression Regulation Neoplastic Cell Transformation Neoplastic Cancer research Heterografts Chromatin immunoprecipitation Neoplasm Transplantation |
| Zdroj: | Europe PubMed Central |
| ISSN: | 1468-3288 0017-5749 |
| Popis: | Objective Gastric cancer (GC) is a deadly malignancy for which new therapeutic strategies are needed. Three transcription factors, KLF5, GATA4 and GATA6, have been previously reported to exhibit genomic amplification in GC. We sought to validate these findings, investigate how these factors function to promote GC, and identify potential treatment strategies for GCs harbouring these amplifications. Design KLF5 , GATA4 and GATA6 copy number and gene expression was examined in multiple GC cohorts. Chromatin immunoprecipitation with DNA sequencing was used to identify KLF5/GATA4/GATA6 genomic binding sites in GC cell lines, and integrated with transcriptomics to highlight direct target genes. Phenotypical assays were conducted to assess the function of these factors in GC cell lines and xenografts in nude mice. Results KLF5 , GATA4 and GATA6 amplifications were confirmed in independent GC cohorts. Although factor amplifications occurred in distinct sets of GCs, they exhibited significant mRNA coexpression in primary GCs, consistent with KLF5/GATA4/GATA6 cross-regulation. Chromatin immunoprecipitation with DNA sequencing revealed a large number of genomic sites co-occupied by KLF5 and GATA4/GATA6, primarily located at gene promoters and exhibiting higher binding strengths. KLF5 physically interacted with GATA factors, supporting KLF5/GATA4/GATA6 cooperative regulation on co-occupied genes. Depletion and overexpression of these factors, singly or in combination, reduced and promoted cancer proliferation, respectively, in vitro and in vivo. Among the KLF5/GATA4/GATA6 direct target genes relevant for cancer development, one target gene, HNF4α , was also required for GC proliferation and could be targeted by the antidiabetic drug metformin, revealing a therapeutic opportunity for KLF5/GATA4/GATA6 amplified GCs. Conclusions KLF5/GATA4/GATA6 may promote GC development by engaging in mutual crosstalk, collaborating to maintain a pro-oncogenic transcriptional regulatory network in GC cells. |
| Databáze: | OpenAIRE |
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