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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 ? 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.

SUBMITTER: Lin S

PROVIDER: S-EPMC7840950 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Silencing of ATP4B of ATPase H<sup>+</sup>/K<sup>+</sup> Transporting Beta Subunit by Intragenic Epigenetic Alteration in Human Gastric Cancer Cells.

Lin Shuye S Lin Bonan B Wang Xiaoyue X Pan Yuanming Y Xu Qing Q He Jin-Shen JS Gong Wanghua W Xing Rui R He Yuqi Y Guo Lihua L Lu Youyong Y Wang Ji Ming JM Huang Jiaqiang J

Oncology research 20170301 3

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 intragen ...[more]

PMID: 28281974

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Project description:Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) is characterized by diffuse alveolar damage and significant edema accumulation, which is associated with impaired alveolar fluid clearance (AFC) and alveolar-capillary barrier disruption, leading to acute respiratory failure. Our previous data showed that electroporation-mediated gene delivery of the Na+, K+-ATPase β1 subunit not only increased AFC, but also restored alveolar barrier function through upregulation of tight junction proteins, leading to treatment of LPS-induced ALI in mice. More importantly, our recent publication showed that gene delivery of MRCKα, the downstream effector of β1 subunit-mediated signaling towards upregulation of adhesive junctions and epithelial and endothelial barrier integrity, also provided therapeutic potential for ARDS treatment in vivo but without necessarily accelerating AFC, indicating that for ARDS treatment, improving alveolar capillary barrier function may be of more benefit than improving fluid clearance. In the present study, we investigated the therapeutical potential of β2 and β3 subunits, the other two β isoforms of Na+, K+-ATPase, for LPS-induced ALI. We found that gene transfer of either the β1, β2, or β3 subunits significantly increased AFC compared to the basal level in naïve animals and each gave similar increased AFC to each other. However, unlike that of the β1 subunit, gene transfer of the β2 or β3 subunit into pre-injured animal lungs failed to show the beneficial effects of attenuated histological damage, neutrophil infiltration, overall lung edema, or increased lung permeability, indicating that β2 or β3 gene delivery could not treat LPS induced lung injury. Further, while β1 gene transfer increased levels of key tight junction proteins in the lungs of injured mice, that of either the β2 or β3 subunit had no effect on levels of tight junction proteins. Taken together, this strongly suggests that restoration of alveolar-capillary barrier function alone may be of equal or even more benefit than improving AFC for ALI/ARDS treatment.

Dataset Information

Silencing of ATP4B of ATPase H⁺/K⁺ Transporting Beta Subunit by Intragenic Epigenetic Alteration in Human Gastric Cancer Cells.

Publications

Silencing of ATP4B of ATPase H<sup>+</sup>/K<sup>+</sup> Transporting Beta Subunit by Intragenic Epigenetic Alteration in Human Gastric Cancer Cells.

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Dataset Information

Silencing of ATP4B of ATPase H+/K+ Transporting Beta Subunit by Intragenic Epigenetic Alteration in Human Gastric Cancer Cells.

Publications

Silencing of ATP4B of ATPase H<sup>+</sup>/K<sup>+</sup> Transporting Beta Subunit by Intragenic Epigenetic Alteration in Human Gastric Cancer Cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Silencing of ATP4B of ATPase H⁺/K⁺ Transporting Beta Subunit by Intragenic Epigenetic Alteration in Human Gastric Cancer Cells.