Alteration of DNA methyltransferases contributes to 5'CpG methylation and poor prognosis in lung cancer

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Title:	Alteration of DNA methyltransferases contributes to 5'CpG methylation and poor prognosis in lung cancer
Authors:	(Ruo-Kai Lin);(Han-Shui Hsu);(Jer-Wei Chang);陳志毅(Chih-Yi Chen);(Jung-Ta Chen);(Yi-Ching Wang)
Contributors:	健康照護學院二年制呼吸治療學系學士班在職專班;中國附醫癌症中心
Keywords:	DNMT;MeCP2;5′CpG hypermethylation;NSCLC;Immunohistochemistry;Tissue chromatin immunoprecipitation
Date:	2007
Issue Date:	2009-08-25 15:49:10 (UTC+8)
Abstract:	Overexpression of DNA methyltransferases DNMT1, DNMT3a and DNMT3b has been reported in various cancers. However, physical binding of DNA methyltransferase (DNMT) to the hypermethylated promoter of tumor suppressor genes (TSGs) has never been demonstrated in tumor tissues. In addition, alteration of DNMT at the protein level has never been reported in the same series of cancer patients. By immunohistochemical analysis, we demonstrated that DNMT1, DNMT3a and DNMT3b proteins were highly expressed in a coordinate manner in lung tumors, particularly in smokers (P = 0.037, by the Fisher exact test). Patients with DNMT1 overexpression had a trend of poorer prognosis than those without such overexpression, and this prognostic significance was apparent in squamous carcinoma (SQ) patients (P = 0.041, by the log-rank test). Both DNMT1 and DNMT3b overexpressions correlated with hypermethylation in the TSG promoters, especially among smoking SQ patients (P = 0.012). To further explore the molecular mechanisms between altered TSGs promoter methylation and overexpression of DNMTs protein, we performed a tissue chromatin-immunoprecipitation polymerase chain reaction assay for lung tumors and showed that the methylated FHIT, p16INK4a and RARβ promoters were bound by both DNMT protein and methyl-CpG-binding protein 2. These data suggest that overexpression and strong binding of various DNMTs may result in promoter hypermethylation of multiple TSGs and ultimately lead to lung tumorigenesis and poor prognosis.
Relation:	LUNG CANCER 55(2)205~213
Appears in Collections:	[Department of Respiratory Therapy] Journal articles

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