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FOXE1 is a target for aberrant methylation in cutaneous squamous cell carcinoma
I Venza1, M Visalli, B Tripodo
1Department of Surgical Specialities, Azienda Ospedaliera Universitaria G. Martino, Via Consolare Valeria, 1 (Gazzi) 98125, Messina, Italy.
Background:
Several cancer-related genes are silenced by promoter hypermethylation in skin cancers. However, to date the somatic epigenetic events that occur in cutaneous squamous cell carcinoma (SCC) tumorigenesis have not been well defined.
Objectives:
To examine epigenetic abnormalities of FOXE1, a gene located on chromosome 9q22, a region frequently lost in SCC.
Methods:
We investigated the methylation status of FOXE1 in 60 cases of cutaneous SCC by methylation-specific polymerase chain reaction, and comparatively examined mRNA and protein expression by real-time polymerase chain reaction and Western blot, respectively.
Results:
We found a higher frequency of FOXE1 promoter hypermethylation in SCCs (55%), as compared with the adjacent uninvolved skin (12%) and blood control samples (9.5%). FOXE1 methylation was frequently seen in association with a complete absence of or downregulated gene expression. Treatment with the demethylating agent 5-Aza-2'-deoxycytidine resulted in profound reactivation of FOXE1 expression.
Conclusions:
These results indicate that FOXE1 is a crucial player in development of cutaneous SCC.
Insights
FOXE1 gene promoter hypermethylation frequently silences FOXE1 in cutaneous squamous cell carcinoma (SCC), impacting gene expression. Demethylation treatment reactivated FOXE1, indicating its crucial role in SCC development.
Area of Science:
- Epigenetics
- Oncology
- Molecular Biology
Background:
- Promoter hypermethylation is a known mechanism for silencing tumor suppressor genes in various cancers.
- Specific epigenetic alterations in cutaneous squamous cell carcinoma (SCC) tumorigenesis remain incompletely understood.
Purpose of the Study:
- To investigate epigenetic dysregulation of the FOXE1 gene in cutaneous SCC.
- To determine the methylation status and expression levels of FOXE1 in SCC and adjacent normal tissues.
Main Methods:
- Methylation-specific PCR was used to assess FOXE1 promoter methylation in 60 SCC samples.
- Real-time PCR and Western blotting were employed to evaluate mRNA and protein expression.
- The effect of the demethylating agent 5-Aza-2'-deoxycytidine on FOXE1 expression was examined.
Main Results:
- FOXE1 promoter hypermethylation was observed in 55% of SCCs, significantly higher than in adjacent skin (12%) and blood (9.5%).
- Hypermethylation correlated with reduced or absent FOXE1 mRNA and protein expression.
- Treatment with 5-Aza-2'-deoxycytidine led to significant reactivation of FOXE1 expression.
Conclusions:
- FOXE1 promoter hypermethylation is a frequent epigenetic event in cutaneous SCC.
- Epigenetic silencing of FOXE1 contributes to SCC development.
- FOXE1 is identified as a critical gene in the pathogenesis of cutaneous SCC.
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