BORIS/CTCFL-mediated transcriptional regulation of the hTERT telomerase gene in testicular and ovarian tumor cells.
Telomerase activity, not detectable in somatic cells but frequently activated during carcinogenesis, confers immortality to tumors. Mechanisms governing expression of the catalytic subunit hTERT, the limiting factor for telomerase activity, still remain unclear. We previously proposed a model in which the binding of the transcription factor CTCF to the two first exons of hTERT results in transcriptional inhibition in normal cells. This inhibition is abrogated, however, by methylation of CTCF binding sites in 85% of tumors. Here, we showed that hTERT was unmethylated in testicular and ovarian tumors and in derivative cell lines. We demonstrated that CTCF and its paralogue, BORIS/CTCFL, were both present in the nucleus of the same cancer cells and bound to the first exon of hTERT in vivo. Moreover, exogenous BORIS expression in normal BORIS-negative cells was sufficient to activate hTERT transcription with an increasing number of cell passages. Thus, expression of BORIS was sufficient to allow hTERT transcription in normal cells and to counteract the inhibitory effect of CTCF in testicular and ovarian tumor cells. These results define an important contribution of BORIS to immortalization during tumorigenesis.
Renaud
Stéphanie
S
Institute of Pathology, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.
Loukinov
Dmitri
D
Alberti
Loredana
L
Vostrov
Alexander
A
Kwon
Yoo-Wook
YW
Bosman
Fred T
FT
Lobanenkov
Victor
V
Benhattar
Jean
J
D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005091:Exons; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D008297:Male; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism; D019098:Telomerase / Q000235:genetics*; D013736:Testicular Neoplasms / Q000235:genetics* / Q000378:metabolism
C456540:CTCFL protein, human; D004268:DNA-Binding Proteins; D019098:Telomerase