title: Regulatory crosstalk between lineage-survival oncogenes KLF5, GATA4 and GATA6 cooperatively promotes gastric cancer development.
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.
  
  
  METHODS
  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.
authors: 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.
authors: Na-Yu
authors: NY
authors: Chia
authors: 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.
authors: Niantao
authors: N
authors: Deng
authors: Cancer and Stem Cell Biology program, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore.
authors: Kakoli
authors: K
authors: Das
authors: Laboratory of Cancer Epigenome, National Cancer Centre, Singapore, Singapore.
authors: Dachuan
authors: D
authors: Huang
authors: 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.
authors: Longyu
authors: L
authors: Hu
authors: Cancer and Stem Cell Biology program, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore.
authors: Yansong
authors: Y
authors: Zhu
authors: Department of Pathology, Singapore General Hospital, Singapore, Singapore.
authors: Kiat Hon
authors: KH
authors: Lim
authors: Cellular and Molecular Research, National Cancer Centre, Singapore, Singapore.
authors: Ming-Hui
authors: MH
authors: Lee
authors: Cellular and Molecular Research, National Cancer Centre, Singapore, Singapore.
authors: Jeanie
authors: J
authors: Wu
authors: Department of Pathology, Singapore General Hospital, Singapore, Singapore.
authors: Xin Xiu
authors: XX
authors: Sam
authors: Department of Pathology, Singapore General Hospital, Singapore, Singapore.
authors: Gek San
authors: GS
authors: Tan
authors: Department of Pathology, Singapore General Hospital, Singapore, Singapore.
authors: Wei Keat
authors: WK
authors: Wan
authors: Laboratory of Cancer Epigenome, National Cancer Centre, Singapore, Singapore.
authors: Willie
authors: W
authors: Yu
authors: Laboratory of Cancer Epigenome, National Cancer Centre, Singapore, Singapore.
authors: Anna
authors: A
authors: Gan
authors: Cancer and Stem Cell Biology program, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore.
authors: Angie Lay Keng
authors: AL
authors: Tan
authors: Cancer and Stem Cell Biology program, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore.
authors: Su-Ting
authors: ST
authors: Tay
authors: Department of Surgical Oncology, National Cancer Centre, Singapore, Singapore.
authors: Khee Chee
authors: KC
authors: Soo
authors: Dept of General Surgery, Singapore General Hospital, Singapore, Singapore.
authors: Wai Keong
authors: WK
authors: Wong
authors: Dept of General Surgery, Singapore General Hospital, Singapore, Singapore.
authors: Lourdes Trinidad M
authors: LT
authors: Dominguez
authors: Genome Institute of Singapore, Singapore, Singapore.
authors: Huck-Hui
authors: HH
authors: Ng
authors: 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.
authors: Steve
authors: S
authors: Rozen
authors: 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.
authors: Liang-Kee
authors: LK
authors: Goh
authors: Cancer and Stem Cell Biology program, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore Laboratory of Cancer Epigenome, National Cancer Centre, Singapore, Singapore.
authors: Bin-Tean
authors: BT
authors: Teh
authors: 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.
authors: Patrick
authors: P
authors: Tan
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D050991:GATA4 Transcription Factor / Q000096:biosynthesis / Q000235:genetics*; D050993:GATA6 Transcription Factor / Q000096:biosynthesis / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D064593:Heterografts; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009857:Oncogenes / Q000235:genetics; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; C492214:KLF5 protein, human; D051741:Kruppel-Like Transcription Factors
keywords: Gastric Cancer