TY  - EJOU
AU  - Lin, Shuye 
AU  - Lin, Bonan 
AU  - Wang, Xiaoyue 
AU  - Pan, Yuanming 
AU  - Xu, Qing 
AU  - He, Jin-Shen 
AU  - Gong, Wanghua 
AU  - Xing, Rui 
AU  - He, Yuqi 
AU  - Guo, Lihua 
AU  - Lu, Youyong 
AU  - Wang, Ji Ming 
AU  - Huang, Jiaqiang 

TI  - Silencing of ATP4B of ATPase H<sup>+</sup>/K<sup>+</sup> Transporting Beta Subunit by Intragenic Epigenetic  Alteration in Human Gastric Cancer Cells
T2  - Oncology Research

PY  - 2017
VL  - 25
IS  - 3
SN  - 1555-3906

AB  - The ATPase H<sup>+</sup>/K<sup>+</sup>
 Transporting Beta Subunit (ATP4B) encodes the b subunit of the gastric H<sup>+</sup>, K<sup>+</sup>
-ATPase, 
which controls gastric acid secretion and is therefore a target for acid reduction. Downregulation of ATP4B was 
recently observed in human gastric cancer (GC) without known mechanisms. In the present study, we demonstrated that ATP4B expression was decreased in human GC tissues and cell lines associated with DNA hypermethylation and histone hypoacetylation of histone H3 lysine 9 at its intragenic region close to the transcriptional 
start site. The expression of ATP4B was restored in GC cell lines by treatment with the DNA methyltransferase 
inhibitor, 5-aza-2'-deoxycytidine (5-AZA), or histone deacetylase inhibitor, trichostatin A (TSA), with further 
enhancement by combined treatment with both drugs. In contrast, 5-AZA had no effect on ATP4B expression 
in human hepatocellular carcinoma (HCC) and pancreatic cancer cell lines, in which ATP4B was silenced and 
accompanied by intragenic methylation. Chromatin immunoprecipitation (ChIP) showed that, in BGC823 GC 
cells, histone H3 lysine 9 acetylation (H3K9ac) was enhanced in the intragenic region of ATP4B upon TSA 
treatment, whereas 5-AZA showed a minimal effect. Additionally, ATP4B expression enhanced the inhibitory 
effects of chemotherapeutic mediation docetaxel on GC cell growth. Thus, as opposed to HCC and pancreatic 
cancer cells, the silencing of ATP4B in GC cells is attributable to the interplay between intragenic DNA methylation and histone acetylation of ATP4B, the restoration of which is associated with a favorable anticancer 
effect of docetaxel. These results have implications for targeting epigenetic alteration at the intragenic region 
of ATP4B in GC cells to benefit diagnosis and treatment of GC.
KW  - ATP4B; Gastric cancer (GC); Intragenic DNA methylation;  Histone modification; Biomarker

DO  - 10.3727/096504016X14734735156265