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Regulatory crosstalk between lineage-survival oncogenes KLF5, GATA4 and GATA6 cooperatively promotes gastric cancer development
  1. Na-Yu Chia1,2,
  2. Niantao Deng1,3,
  3. Kakoli Das1,
  4. Dachuan Huang4,
  5. Longyu Hu1,5,
  6. Yansong Zhu1,
  7. Kiat Hon Lim6,
  8. Ming-Hui Lee7,
  9. Jeanie Wu7,
  10. Xin Xiu Sam6,
  11. Gek San Tan6,
  12. Wei Keat Wan6,
  13. Willie Yu4,
  14. Anna Gan4,
  15. Angie Lay Keng Tan1,
  16. Su-Ting Tay1,
  17. Khee Chee Soo8,
  18. Wai Keong Wong9,
  19. Lourdes Trinidad M Dominguez9,
  20. Huck-Hui Ng10,
  21. Steve Rozen1,2,
  22. Liang-Kee Goh1,11,
  23. Bin-Tean Teh1,4,
  24. Patrick Tan1,5,7,10
  1. 1Cancer and Stem Cell Biology program, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore
  2. 2A*STAR-Duke-NUS Neuroscience Partnership, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore
  3. 3NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore
  4. 4Laboratory of Cancer Epigenome, National Cancer Centre, Singapore, Singapore
  5. 5Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
  6. 6Department of Pathology, Singapore General Hospital, Singapore, Singapore
  7. 7Cellular and Molecular Research, National Cancer Centre, Singapore, Singapore
  8. 8Department of Surgical Oncology, National Cancer Centre, Singapore, Singapore
  9. 9Dept of General Surgery, Singapore General Hospital, Singapore, Singapore
  10. 10Genome Institute of Singapore, Singapore, Singapore
  11. 11Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
  1. Correspondence to Dr Patrick Tan, Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School Singapore, 8 College Road, Singapore 169857, Singapore; gmstanp{at}duke-nus.edu.sg

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.

  • Gastric Cancer

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