title: DLEC1 is a functional 3p22.3 tumour suppressor silenced by promoter CpG methylation in colon and gastric cancers.
abstract: Promoter CpG methylation of tumour suppressor genes (TSGs) is an epigenetic biomarker for TSG identification and molecular diagnosis. We screened genome wide for novel methylated genes through methylation subtraction of a genetic demethylation model of colon cancer (double knockout of DNMT1 and DNMT3B in HCT116) and identified DLEC1 (Deleted in lung and oesophageal cancer 1), a major 3p22.3 TSG, as one of the methylated targets. We further found that DLEC1 was downregulated or silenced in most colorectal and gastric cell lines due to promoter methylation, whereas broadly expressed in normal tissues including colon and stomach, and unmethylated in expressing cell lines and immortalised normal colon epithelial cells. DLEC1 expression was reactivated through pharmacologic or genetic demethylation, indicating a DNMT1/DNMT3B-mediated methylation silencing. Aberrant methylation was further detected in primary colorectal (10 out of 34, 29%) and gastric tumours (30 out of 89, 34%), but seldom in paired normal colon (0 out of 17) and gastric (1 out of 20, 5%) samples. No correlation between DLEC1 methylation and clinical parameters of gastric cancers was found. Ectopic expression of DLEC1 in silenced HCT116 and MKN45 cells strongly inhibited their clonogenicity. Thus, DLEC1 is a functional tumour suppressor, being frequently silenced by epigenetic mechanism in gastrointestinal tumours.
authors.affiliation: Department of Clinical Oncology, State Key Laboratory in Oncology in South China, Sir YK Pao Center for Cancer, Hong Kong Cancer Institute, Chinese University of Hong Kong, Shatin, Hong Kong, China. jmying@hotmail.com
authors.forename: J
authors.initials: J
authors.lastname: Ying
authors.forename: F F
authors.initials: FF
authors.lastname: Poon
authors.forename: J
authors.initials: J
authors.lastname: Yu
authors.forename: H
authors.initials: H
authors.lastname: Geng
authors.forename: A H Y
authors.initials: AH
authors.lastname: Wong
authors.forename: G-H
authors.initials: GH
authors.lastname: Qiu
authors.forename: H K
authors.initials: HK
authors.lastname: Goh
authors.forename: S Y
authors.initials: SY
authors.lastname: Rha
authors.forename: L
authors.initials: L
authors.lastname: Tian
authors.forename: A T C
authors.initials: AT
authors.lastname: Chan
authors.forename: J J Y
authors.initials: JJ
authors.lastname: Sung
authors.forename: Q
authors.initials: Q
authors.lastname: Tao
mesh_terms: D045744:Cell Line, Tumor; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics / Q000378:metabolism; D003106:Colon / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008297:Male; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C119064:DLEC1 protein, human; D025521:Tumor Suppressor Proteins