Faculty Collaboration Database

Aberrant promoter methylation and silencing of the POU2F3 gene in cervical cancer. Oncogene 2006 Aug 31;25(39):5436-45

Date

04/12/2006

Pubmed ID

16607278

DOI

10.1038/sj.onc.1209530

Scopus ID

2-s2.0-33748324638 (requires institutional sign-in at Scopus site)   34 Citations

Abstract

POU2F3 (OCT11, Skn-1a) is a keratinocyte-specific POU transcription factor whose expression is tied to squamous epithelial stratification. It is also a candidate tumor suppressor gene in cervical cancer (CC) because it lies in a critical loss of heterozygosity region on 11q23.3 in that cancer, and its expression is lost in more than 50% of CC tumors and cell lines. We now report that the loss of POU2F3 expression is tied to the hypermethylation of CpG islands in the POU2F3 promoter. Bisulfite sequencing analysis revealed that methylation of specific CpG sites (-287 to -70 bp) correlated with POU2F3 expression, which could be reactivated with a demethylating agent. Combined bisulfite restriction analysis revealed aberrant methylation of the POU2F3 promoter in 18 of 46 (39%) cervical tumors but never in normal epithelium. POU2F3 expression was downregulated and inversely correlated with promoter hypermethylation in 10 out of 11 CC cell lines. Immunohistochemical analysis on a cervical tissue microarray detected POU2F3 protein in the epithelium above the basal layer. As the disease progressed, expression also decreased, especially in invasive squamous cell cancer (70% loss). Thus, aberrant DNA methylation of the CpG island in POU2F3 promoter appears to play a key role in silencing this gene expression in human CC. The results suggested that POU2F3 might be one of the CC-related tumor suppressor genes, which are disrupted by both epigenetic and genetic mechanisms.

Author List

Zhang Z, Huettner PC, Nguyen L, Bidder M, Funk MC, Li J, Rader JS

Author

Janet Sue Rader MD Chair, Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenocarcinoma
Biopsy
Carcinoma, Squamous Cell
Cell Line, Tumor
DNA Methylation
DNA Primers
Female
Gene Expression Regulation, Neoplastic
Gene Silencing
Genes, Tumor Suppressor
Genome, Human
Homeodomain Proteins
Humans
Oligonucleotide Array Sequence Analysis
POU Domain Factors
Promoter Regions, Genetic
Restriction Mapping
Uterine Cervical Neoplasms