Aberrant JAK/STAT Signaling Suppresses TFF1 and TFF2 through Epigenetic Silencing of GATA6 in Gastric Cancer.
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.
Department of Gastroenterology and Hepatology, Chiayi Chang Gung Memorial Hospital, Chiayi 613, Taiwan. minjyun@cloud.cgmh.org.tw.
Cheng-Shyong
CS
Wu
Department of Gastroenterology and Hepatology, Chiayi Chang Gung Memorial Hospital, Chiayi 613, Taiwan. wkliang@cgmh.org.tw.
Kuo-Liang
KL
Wei
Department of Gastroenterology and Hepatology, Chiayi Chang Gung Memorial Hospital, Chiayi 613, Taiwan. alien711021@gmail.com.
Jian-Liang
JL
Chou
Department of Gastroenterology and Hepatology, Chiayi Chang Gung Memorial Hospital, Chiayi 613, Taiwan. cmusickimo@yahoo.com.tw.
Chung-Kuang
CK
Lu
Department of Surgery, Chiayi Chang Gung Memorial Hospital, Chiayi 613, Taiwan. p12155@cgmh.org.tw.
Ching-Chuan
CC
Hsieh
Department of Life Science, National Chung Cheng University, 168 University Road, Min Hsiung, Chiayi 621, Taiwan. a584919@gmail.com.
Jora M J
JM
Lin
Department of Gastroenterology and Hepatology, Chiayi Chang Gung Memorial Hospital, Chiayi 613, Taiwan. evonne8006@cgmh.org.tw.
Yi-Fang
YF
Deng
Department of Life Science, National Chung Cheng University, 168 University Road, Min Hsiung, Chiayi 621, Taiwan. white8020@hotmail.com.
Wan-Ting
WT
Hsu
Department of Fragrance and Cosmetic Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan. davidw@kmu.edu.tw.
Hui-Min David
HM
Wang
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China. duncanleung@umac.mo.
Chung-Hang
CH
Leung
Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China. edmondma@hkbu.edu.hk.
Dik-Lung
DL
Ma
Department of Life Science, National Chung Cheng University, 168 University Road, Min Hsiung, Chiayi 621, Taiwan. biocl@ccu.edu.tw.
Chin
C
Li
Department of Life Science, National Chung Cheng University, 168 University Road, Min Hsiung, Chiayi 621, Taiwan. biowyc@ccu.edu.tw.
Michael W Y
MW
Chan
D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D005260:Female; D050993:GATA6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism*; D000071163:Trefoil Factor-1 / Q000235:genetics / Q000378:metabolism*; D000071164:Trefoil Factor-2 / Q000235:genetics / Q000378:metabolism*
D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C051838:TFF1 protein, human; C000604007:TFF2 protein, human; D000071163:Trefoil Factor-1; D000071164:Trefoil Factor-2; D053612:Janus Kinases
GATA6; STAT3; TFF1; TFF2; epigenetic silencing; gastric cancer