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MicroRNA-152 mediates DNMT1-regulated DNA methylation in the estrogen receptor ? gene.

ABSTRACT: BACKGROUND: Estrogen receptor ? (ER?) has been shown to protect against atherosclerosis. Methylation of the ER? gene can reduce ER? expression leading to a higher risk for cardiovascular disease. Recently, microRNAs have been found to regulate DNA methyltransferases (DNMTs) and thus control methylation status in several genes. We first searched for microRNAs involved in DNMT-associated DNA methylation in the ER? gene. We also tested whether statin and a traditional Chinese medicine (San-Huang-Xie-Xin-Tang, SHXXT) could exert a therapeutic effect on microRNA, DNMT and ER? methylation. METHODOLOGY/PRINCIPAL FINDINGS: The ER? expression was decreased and ER? methylation was increased in LPS-treated human aortic smooth muscle cells (HASMCs) and the aorta from rats under a high-fat diet. MicroRNA-152 was found to be down regulated in the LPS-treated HASMCs. We validated that microRNA-152 can knock down DNMT1 in HASMCs leading to hypermethylation of the ER? gene. Statin had no effect on microRNA-152, DNMT1 or ER? expression. On the contrary, SHXXT could restore microRNA-152, decrease DNMT1 and increase ER? expression in both cellular and animal studies. CONCLUSIONS/SIGNIFICANCE: The present study showed that microRNA-152 decreases under the pro-atherosclerotic conditions. The reduced microRNA-152 can lose an inhibitory effect on DNA methyltransferase, which leads to hypermethylation of the ER? gene and a decrease of ER? level. Although statin can not reverse these cascade proatherosclerotic changes, the SHXXT shows a promising effect to inhibit this unwanted signaling pathway.

SUBMITTER: Wang YS

PROVIDER: S-EPMC3266286 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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MicroRNA-152 mediates DNMT1-regulated DNA methylation in the estrogen receptor α gene.

Wang Yung-Song YS Chou Wen-Wen WW Chen Ku-Chung KC Cheng Hsin-Yun HY Lin Ruey-Tay RT Juo Suh-Hang Hank SH

PloS one 20120125 1

<h4>Background</h4>Estrogen receptor α (ERα) has been shown to protect against atherosclerosis. Methylation of the ERα gene can reduce ERα expression leading to a higher risk for cardiovascular disease. Recently, microRNAs have been found to regulate DNA methyltransferases (DNMTs) and thus control methylation status in several genes. We first searched for microRNAs involved in DNMT-associated DNA methylation in the ERα gene. We also tested whether statin and a traditional Chinese medicine (San-H ...[more]

PMID: 22295098

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Project description:Alterations in the global methylation of DNA and in specific regulatory genes are two epigenetic alterations found in cancer. However, the significance of epigenetic changes for diagnosis and/or prognosis of colorectal cancer have not been established, although it has been extensively investigated. Recently we have identified a new type of cancer cell called precancerous stem cells (pCSCs) and proposed that cancer may arise from a lengthy development process of tumor initiating cells (TICs) --> pCSCs --> cancer stem cells (CSCs) --> cancer, which is in parallel to histological changes of hyperplasia (TICs) --> precancer (pCSCs) --> carcinoma (CSCs/cancer cells), accompanied by clonal evolutionary epigenetic and genetic alterations. In this study, we investigated whether aberrant DNA methylation can be used as a biomarker for the differentiation between premalignant and malignant lesions in the colorectum. The profile of global DNA and estrogen receptor (ER)-alpha gene methylation during cancer development was determined by analysis of 5-methylcytosine (5-MeC) using immunohistochemical (IHC) staining, dot blot analysis or a quantitative gene methylation assay (QGMA). Herein we show that global DNA hypomethylation and ER-alpha gene hypermethylation are progressively enhanced from hyperplastic polyps (HPs) --> adenomatous polyps (APs) --> adenomatous carcinoma (AdCa). The aberrant methylation can be completely reversed in APs, but not in AdCa by a nonsteroidal anti-inflammatory drug (NSAID) celecoxib, which is a selective inhibitor of cyclooxygenase-2 (Cox-2), suggesting that the epigenetic alterations between colorectal precancer (AP) and cancer (AdCa) are fundamentally different in response to anti-cancer therapy. In normal colorectal mucosa, while global DNA methylation was not affected by aging, ER-alpha gene methylation was significantly increased with aging. However, this increase did not reach the level observed in colorectal APs. Taken together, reversibility of aberrant global DNA and ER-alpha gene methylation distinguishes colorectal precancer from cancer.

Dataset Information

MicroRNA-152 mediates DNMT1-regulated DNA methylation in the estrogen receptor ? gene.

Publications

MicroRNA-152 mediates DNMT1-regulated DNA methylation in the estrogen receptor α gene.

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