Aberrant JAK/STAT signaling suppresses TFF1 and TFF2 through epigenetic silencing of GATA6 in gastric cancer

Cheng Shyong Wu, Kuo Liang Wei, Jian Liang Chou, Chung Kuang Lu, Ching Chuan Hsieh, Jora M.J. Lin, Yi Fang Deng, Wan Ting Hsu, Hui Min David Wang, Chung Hang Leung, Edmond Dik Lung MA, Chin Li, Michael W.Y. Chan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

Aberrant Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling is crucial to the development of gastric cancer. In this study, we examined the role of STAT3 in the expression and methylation of its targets in gastric cancer patients. Results from RNA sequencing identified an inverse correlation between the expression of STAT3 and GATA6 in 23 pairs of gastric cancer patient samples. We discovered that the expression of GATA6 is epigenetically silenced through promoter methylation in gastric cancer cell lines. Interestingly, the inhibition of STAT3 using a novel STAT3 inhibitor restored the expression of GATA6 and its targets, trefoil factors 1 and 2 (TFF1/2). Moreover, disruption of STAT3 binding to GATA6 promoter by small hairpin RNA restored GATA6 expression in AGS cells. A clinically significant correlation was also observed between the expression of GATA6 and TFF1/2 among tissue samples from 60 gastric cancer patients. Finally, bisulfite pyrosequencing revealed GATA6 methylation in 65% (39/60) of the patients, and those with higher GATA6 methylation tended to have shorter overall survival. In conclusion, we demonstrated that aberrant JAK/STAT signaling suppresses TFF1/2 partially through the epigenetic silencing of GATA6. Therapeutic intervention of STAT3 in reversing the epigenetic status of GATA6 could benefit the treatment of gastric cancer and is worthy of further investigation.

Original languageEnglish
Article number1467
JournalInternational Journal of Molecular Sciences
Volume17
Issue number9
DOIs
Publication statusPublished - 2 Sep 2016

Scopus Subject Areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

User-Defined Keywords

  • Epigenetic silencing
  • Gastric cancer
  • GATA6
  • STAT3
  • TFF1
  • TFF2

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