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Aberrant promoter methylation and silencing of the POU2F3 gene in cervical cancer

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 on11q23.3 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.

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Acknowledgements

This research was supported by National Institutes of Health (NIH) Grant CA94141-04. We thank Dr FT Kraus for his generous advice on immunohistochemistry. Margo C Funk was supported by the Howard Hughes Medical Institute. We also thank the Alvin J Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St Louis, MO, for the use of the Tissue Procurement Core that provided the tissue array. The Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant No. P30 CA91842.

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Zhang, Z., Huettner, P., Nguyen, L. et al. Aberrant promoter methylation and silencing of the POU2F3 gene in cervical cancer. Oncogene 25, 5436–5445 (2006). https://doi.org/10.1038/sj.onc.1209530

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Keywords

  • POU2F3
  • promoter
  • hypermethylation
  • cervical cancer

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