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Regulatory crosstalk between lineage-survival oncogenes KLF5, GATA4 and GATA6 cooperatively promotes gastric cancer development.
- Source :
-
Gut [Gut] 2015 May; Vol. 64 (5), pp. 707-19. Date of Electronic Publication: 2014 Jul 22. - Publication Year :
- 2015
-
Abstract
- 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.<br />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.<br />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.<br />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.<br /> (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)
- Subjects :
- Animals
Cell Proliferation
Cell Transformation, Neoplastic genetics
Cell Transformation, Neoplastic metabolism
GATA4 Transcription Factor biosynthesis
GATA6 Transcription Factor biosynthesis
Gene Expression Profiling methods
Gene Silencing
Genetic Predisposition to Disease
Heterografts
Humans
Kruppel-Like Transcription Factors biosynthesis
Mice, Nude
Neoplasm Transplantation
Oncogenes genetics
Promoter Regions, Genetic
Stomach Neoplasms metabolism
Stomach Neoplasms pathology
Tumor Cells, Cultured
GATA4 Transcription Factor genetics
GATA6 Transcription Factor genetics
Gene Expression Regulation, Neoplastic genetics
Kruppel-Like Transcription Factors genetics
Stomach Neoplasms genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1468-3288
- Volume :
- 64
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Gut
- Publication Type :
- Academic Journal
- Accession number :
- 25053715
- Full Text :
- https://doi.org/10.1136/gutjnl-2013-306596