Na-Yu Chia1, Niantao Deng2, Kakoli Das3, Dachuan Huang4, Longyu Hu5, Yansong Zhu3, Kiat Hon Lim6, Ming-Hui Lee7, Jeanie Wu7, Xin Xiu Sam6, Gek San Tan6, Wei Keat Wan6, Willie Yu4, Anna Gan4, Angie Lay Keng Tan3, Su-Ting Tay3, Khee Chee Soo8, Wai Keong Wong9, Lourdes Trinidad M Dominguez9, Huck-Hui Ng10, Steve Rozen1, Liang-Kee Goh11, Bin-Tean Teh12, Patrick Tan13. 1. Cancer and Stem Cell Biology program, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore A*STAR-Duke-NUS Neuroscience Partnership, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore. 2. Cancer and Stem Cell Biology program, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore. 3. Cancer and Stem Cell Biology program, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore. 4. Laboratory of Cancer Epigenome, National Cancer Centre, Singapore, Singapore. 5. Cancer and Stem Cell Biology program, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. 6. Department of Pathology, Singapore General Hospital, Singapore, Singapore. 7. Cellular and Molecular Research, National Cancer Centre, Singapore, Singapore. 8. Department of Surgical Oncology, National Cancer Centre, Singapore, Singapore. 9. Dept of General Surgery, Singapore General Hospital, Singapore, Singapore. 10. Genome Institute of Singapore, Singapore, Singapore. 11. Cancer and Stem Cell Biology program, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore. 12. Cancer and Stem Cell Biology program, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore Laboratory of Cancer Epigenome, National Cancer Centre, Singapore, Singapore. 13. Cancer and Stem Cell Biology program, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore Cellular and Molecular Research, National Cancer Centre, Singapore, Singapore Genome Institute of Singapore, Singapore, Singapore.
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. 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. 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.
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. 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.
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