DNA methylation-dependent regulation of BORIS/CTCFL expression in ovarian cancer.
Brother of the Regulator of Imprinted Sites (BORIS/CTCFL) is an autosomal cancer germline (CG) or cancer-testis antigen gene and paralog of CTCF that has been proposed to function as an oncogene in human cancer via dysregulation of the cancer epigenome. Here we show that genetic disruption of DNA methylation in human cancer cells induces BORIS expression, coincident with DNA hypomethylation and an altered histone H3 modification pattern at the BORIS promoter. Rapid amplification of cDNA ends (RACE) mapping revealed that the transcriptional start site of BORIS in human testis, DNMT deficient human cancer cells, and human epithelial ovarian cancer (EOC) tissues, is similar and lies within the 5' CpG island. The BORIS promoter is repressed by CpG methylation in a dose-dependent fashion, indicating a direct role for DNA methylation in BORIS transcriptional regulation. In human ovarian cancer cell lines, 5-aza-2'-deoxycytidine treatment activates BORIS expression and reduces BORIS promoter DNA methylation. We quantitatively measured BORIS mRNA expression and promoter DNA methylation in normal ovary (NO; n = 10) and epithelial ovarian cancer (EOC; n = 77) and found that, compared to NO, EOC tumors show increased BORIS expression and decreased BORIS methylation. Importantly, BORIS promoter DNA methylation shows a significant inverse correlation with BORIS mRNA expression in EOC (Kendall's Tau = -0.235, P = 0.007, n = 63). These data establish promoter DNA hypomethylation as a mechanism leading to BORIS expression in human ovarian cancer.
Woloszynska-Read
Anna
A
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
James
Smitha R
SR
Link
Petra A
PA
Yu
Jihnhee
J
Odunsi
Kunle
K
Karpf
Adam R
AR
D045744:Cell Line, Tumor; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000172:deficiency; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009928:Organ Specificity; D010051:Ovarian Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic; D024363:Transcription Initiation Site
C456540:CTCFL protein, human; D004268:DNA-Binding Proteins; D004248:DNA (Cytosine-5-)-Methyltransferases