title: Candidate tumor-suppressor gene DLEC1 is frequently downregulated by promoter hypermethylation and histone hypoacetylation in human epithelial ovarian cancer.
abstract: Suppression of ovarian tumor growth by chromosome 3p was demonstrated in a previous study. Deleted in Lung and Esophageal Cancer 1 (DLEC1) on 3p22.3 is a candidate tumor suppressor in lung, esophageal, and renal cancers. The potential involvement of DLEC1 in epithelial ovarian cancer remains unknown. In the present study, DLEC1 downregulation was found in ovarian cancer cell lines and primary ovarian tumors. Focus-expressed DLEC1 in two ovarian cancer cell lines resulted in 41% to 52% inhibition of colony formation. No chromosomal loss of chromosome 3p22.3 in any ovarian cancer cell line or tissue was found. Promoter hypermethylation of DLEC1 was detected in ovarian cancer cell lines with reduced DLEC1 transcripts, whereas methylation was not detected in normal ovarian epithelium and DLEC1-expressing ovarian cancer cell lines. Treatment with demethylating agent enhanced DLEC1 expression in 90% (9 of 10) of ovarian cancer cell lines. DLEC1 promoter methylation was examined in 13 high-grade ovarian tumor tissues with DLEC1 downregulation, in which 54% of the tumors showed DLEC1 methylation. In addition, 80% of ovarian cancer cell lines significantly upregulated DLEC1 transcripts after histone deacetylase inhibitor treatment. Therefore, our results suggested that DLEC1 suppressed the growth of ovarian cancer cells and that its downregulation was closely associated with promoter hypermethylation and histone hypoacetylation.
authors.affiliation: Laboratory of Gynecologic Oncology, Division of Gynecology Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. jkwong@rics.bwh.harvard.edu
authors.forename: Joseph
authors.initials: J
authors.lastname: Kwong
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Kwong-Kwok
authors.initials: KK
authors.lastname: Wong
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zhou
authors.forename: David T W
authors.initials: DT
authors.lastname: Wong
authors.forename: Kwok-Wai
authors.initials: KW
authors.lastname: Lo
authors.forename: William R
authors.initials: WR
authors.lastname: Welch
authors.forename: Ross S
authors.initials: RS
authors.lastname: Berkowitz
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Mok
mesh_terms: D045744:Cell Line, Tumor; D019175:DNA Methylation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000737:chemistry*; D006801:Humans; D019656:Loss of Heterozygosity; D010051:Ovarian Neoplasms / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis*; D015854:Up-Regulation
chemical_list: C119064:DLEC1 protein, human; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D025521:Tumor Suppressor Proteins