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Regulatory crosstalk between lineage-survival oncogenes KLF5, GATA4 and GATA6 cooperatively promotes gastric cancer development.

Publication ,  Journal Article
Chia, N-Y; Deng, N; Das, K; Huang, D; Hu, L; Zhu, Y; Lim, KH; Lee, M-H; Wu, J; Sam, XX; Tan, GS; Wan, WK; Yu, W; Gan, A; Tan, ALK; Soo, KC ...
Published in: Gut
May 2015

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.

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Published In

Gut

DOI

EISSN

1468-3288

Publication Date

May 2015

Volume

64

Issue

5

Start / End Page

707 / 719

Location

England

Related Subject Headings

  • Tumor Cells, Cultured
  • Stomach Neoplasms
  • Promoter Regions, Genetic
  • Oncogenes
  • Neoplasm Transplantation
  • Mice, Nude
  • Kruppel-Like Transcription Factors
  • Humans
  • Heterografts
  • Genetic Predisposition to Disease
 

Citation

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Chia, N.-Y., Deng, N., Das, K., Huang, D., Hu, L., Zhu, Y., … Tan, P. (2015). Regulatory crosstalk between lineage-survival oncogenes KLF5, GATA4 and GATA6 cooperatively promotes gastric cancer development. Gut, 64(5), 707–719. https://doi.org/10.1136/gutjnl-2013-306596
Chia, Na-Yu, Niantao Deng, Kakoli Das, Dachuan Huang, Longyu Hu, Yansong Zhu, Kiat Hon Lim, et al. “Regulatory crosstalk between lineage-survival oncogenes KLF5, GATA4 and GATA6 cooperatively promotes gastric cancer development.Gut 64, no. 5 (May 2015): 707–19. https://doi.org/10.1136/gutjnl-2013-306596.
Chia, Na-Yu, et al. “Regulatory crosstalk between lineage-survival oncogenes KLF5, GATA4 and GATA6 cooperatively promotes gastric cancer development.Gut, vol. 64, no. 5, May 2015, pp. 707–19. Pubmed, doi:10.1136/gutjnl-2013-306596.
Chia N-Y, Deng N, Das K, Huang D, Hu L, Zhu Y, Lim KH, Lee M-H, Wu J, Sam XX, Tan GS, Wan WK, Yu W, Gan A, Tan ALK, Tay S-T, Soo KC, Wong WK, Dominguez LTM, Ng H-H, Rozen S, Goh L-K, Teh B-T, Tan P. Regulatory crosstalk between lineage-survival oncogenes KLF5, GATA4 and GATA6 cooperatively promotes gastric cancer development. Gut. 2015 May;64(5):707–719.

Published In

Gut

DOI

EISSN

1468-3288

Publication Date

May 2015

Volume

64

Issue

5

Start / End Page

707 / 719

Location

England

Related Subject Headings

  • Tumor Cells, Cultured
  • Stomach Neoplasms
  • Promoter Regions, Genetic
  • Oncogenes
  • Neoplasm Transplantation
  • Mice, Nude
  • Kruppel-Like Transcription Factors
  • Humans
  • Heterografts
  • Genetic Predisposition to Disease