title: Silencing of ATP4B of ATPase H+/K+Transporting Beta Subunit by Intragenic Epigenetic Alteration in Human Gastric Cancer Cells.
abstract: The ATPase H+/K+ Transporting Beta Subunit (ATP4B) encodes the β subunit of the gastric H+, K+-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.
authors.forename: Shuye
authors.initials: S
authors.lastname: Lin
authors.forename: Bonan
authors.initials: B
authors.lastname: Lin
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Wang
authors.forename: Yuanming
authors.initials: Y
authors.lastname: Pan
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.forename: Jin-Shen
authors.initials: JS
authors.lastname: He
authors.forename: Wanghua
authors.initials: W
authors.lastname: Gong
authors.forename: Rui
authors.initials: R
authors.lastname: Xing
authors.forename: Yuqi
authors.initials: Y
authors.lastname: He
authors.forename: Lihua
authors.initials: L
authors.lastname: Guo
authors.forename: Youyong
authors.initials: Y
authors.lastname: Lu
authors.forename: Ji Ming
authors.initials: JM
authors.lastname: Wang
authors.forename: Jiaqiang
authors.initials: J
authors.lastname: Huang
mesh_terms: D000107:Acetylation / Q000187:drug effects; D001374:Azacitidine / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics*; D057890:Epigenomics / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020868:Gene Silencing / Q000187:drug effects / Q000502:physiology*; D017506:H(+)-K(+)-Exchanging ATPase / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000235:genetics; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008113:Liver Neoplasms / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics*; D024363:Transcription Initiation Site / Q000502:physiology
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D021122:Protein Subunits; C012589:trichostatin A; D017506:H(+)-K(+)-Exchanging ATPase; D001374:Azacitidine