title: Aberrant promoter methylation and expression of UTF1 during cervical carcinogenesis.
abstract: Promoter methylation profiles are proposed as potential prognosis and/or diagnosis biomarkers in cervical cancer. Up to now, little is known about the promoter methylation profile and expression pattern of stem cell (SC) markers during tumor development. In this study, we were interested to identify SC genes methylation profiles during cervical carcinogenesis. A genome-wide promoter methylation screening revealed a strong hypermethylation of Undifferentiated cell Transcription Factor 1 (UTF1) promoter in cervical cancer in comparison with normal ectocervix. By direct bisulfite pyrosequencing of DNA isolated from liquid-based cytological samples, we showed that UTF1 promoter methylation increases with lesion severity, the highest level of methylation being found in carcinoma. This hypermethylation was associated with increased UTF1 mRNA and protein expression. By using quantitative RT-PCR and Western Blot, we showed that both UTF1 mRNA and protein are present in epithelial cancer cell lines, even in the absence of its two main described regulators Oct4A and Sox2. Moreover, by immunofluorescence, we confirmed the nuclear localisation of UTF1 in cell lines. Surprisingly, direct bisulfite pyrosequencing revealed that the inhibition of DNA methyltransferase by 5-aza-2'-deoxycytidine was associated with decreased UTF1 gene methylation and expression in two cervical cancer cell lines of the four tested. These findings strongly suggest that UTF1 promoter methylation profile might be a useful biomarker for cervical cancer diagnosis and raise the questions of its role during epithelial carcinogenesis and of the mechanisms regulating its expression.
authors.affiliation: Laboratory of Experimental Pathology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer, University of Liège, Liège, Belgium. samuel.guenin@gmail.com
authors.forename: Samuel
authors.initials: S
authors.lastname: Guenin
authors.forename: Mustapha
authors.initials: M
authors.lastname: Mouallif
authors.forename: Rachel
authors.initials: R
authors.lastname: Deplus
authors.forename: Xavier
authors.initials: X
authors.lastname: Lampe
authors.forename: Nathalie
authors.initials: N
authors.lastname: Krusy
authors.forename: Emilie
authors.initials: E
authors.lastname: Calonne
authors.forename: Katty
authors.initials: K
authors.lastname: Delbecque
authors.forename: Frederic
authors.initials: F
authors.lastname: Kridelka
authors.forename: François
authors.initials: F
authors.lastname: Fuks
authors.forename: My Mustapha
authors.initials: MM
authors.lastname: Ennaji
authors.forename: Philippe
authors.initials: P
authors.lastname: Delvenne
mesh_terms: D001374:Azacitidine / Q000494:pharmacology; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D002584:Cervix Uteri / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016000:Cluster Analysis; D003584:Cytological Techniques; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics*; D004273:DNA, Neoplasm / Q000302:isolation & purification; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D052138:Genes, Neoplasm / Q000235:genetics; D006801:Humans; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D004273:DNA, Neoplasm; D009687:Nuclear Proteins; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D015534:Trans-Activators; C484738:UTF1 protein, human; D001374:Azacitidine