Journal Article

Modulation of E-cadherin expression by K-Ras; involvement of DNA methyltransferase-3b

Osong Kwon, Sook Jung Jeong, Sun Ok Kim, Long He, Hee Gu Lee, Kyung Lib Jang, Hiroyuki Osada, Mira Jung, Bo Yeon Kim and Jong Seog Ahn

in Carcinogenesis

Volume 31, issue 7, pages 1194-1201
Published in print July 2010 | ISSN: 0143-3334
Published online April 2010 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgq071
Modulation of E-cadherin expression by K-Ras; involvement of DNA methyltransferase-3b

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E-cadherin, as a tumor suppressor, plays an important role for intercellular adhesion involved in metastasis. Although K-Ras is highly expressed in a variety of cancers, the regulation of E-cadherin expression by K-Ras in association with DNA methylation and cell metastasis has not been completely clarified. In this study, E-cadherin expression was repressed in 267B1/K-Ras human epithelial prostate cancer cells stably overexpressing K-Ras, resulting from hypermethylation of E-cadherin promoter as evidenced by methylation-specific polymerase chain reaction (PCR), bisulfite sequencing, real-time reverse transcription–PCR and western blot analysis. The increased level of DNA methyltransferase (DNMT) 3b in 267B1/K-Ras cells was reduced by small interfering RNA-mediated knockdown of k-ras, whereas DNMT1 and DNMT3a did not change regardless of K-Ras or 5-aza-2′-deoxycytidine (5′-AzaC) treatment. Furthermore, binding of DNMT3b to E-cadherin promoter was increased in 267B1/K-Ras cells but was reduced by 5′-AzaC, as revealed by chromatin immunoprecipitation assay, which was in agreement with cell aggregation and invasive mobilization of the cells. Hence, our data suggest that increased binding of DNMT3b to E-cadherin promoter region by K-Ras cause promoter hypermethylation for reduced expression of E-cadherin, leading to the decreased cell aggregation and increased metastasis of human prostate cancer cells overexpressing K-Ras.

Journal Article.  5675 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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