Epigenetic alterations of the keratin 13 gene in oral squamous cell carcinoma

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• 作者：Kaori Naganuma (1) (2)
  Mitsutoki Hatta (1)
  Tetsuro Ikebe (2)
  Jun Yamazaki (1)
  
  1. Department of Physiological Science and Molecular Biology ; Fukuoka Dental College ; Fukuoka ; 814-0193 ; Japan
  2. Department of Oral and Maxillofacial Surgery ; Fukuoka Dental College ; Fukuoka ; 814-0193 ; Japan
  
• 关键词：Keratin 13 (KRT13) ; Oral squamous cell carcinoma (OSCC) ; Polycomb repressive complex 2 (PRC2) ; Gene silencing
• 刊名：BMC Cancer
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：14
• 期：1
• 全文大小：1,109 KB
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  30. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/14/988/prepub
  
• 刊物主题：Cancer Research; Oncology; Stem Cells; Animal Models; Internal Medicine;
• 出版者：BioMed Central
• ISSN：1471-2407

文摘

Background Epigenetic modifications play important roles in the regulation of gene expression determining cellular phenotype as well as various pathologies such as cancer. Although the loss of keratin 13 (KRT13) is reportedly linked to malignant transformation of oral epithelial cells, the molecular mechanisms through which KRT13 is repressed in oral squamous cell carcinoma (OSCC) remain unclear. The aim of this study is to identify the epigenetic alterations of the KRT13 gene in OSCCs. Methods We investigated KRT13 expression levels and chromatin modifications of the KRT13 promoter in the three OSCC cell lines (HSC4, HSC3, and SAS). The expression levels of KRT13 protein and mRNA were analyzed by western blotting and quantitative reverse-transcription polymerase chain reaction, respectively, and the localization of KRT13 protein was detected by immunofluorescence. DNA methylation and histone modifications in the KRT13 promoter were determined by bisulfite sequencing and chromatin immunoprecipitation (ChIP), respectively. For the pharmacological depletion of Polycomb repressive complex 2 (PRC2), cells were treated with 3-deazaneplanocin A (DZNep). Results KRT13 expression was transcriptionally silenced in the HSC3 and SAS cells and post-transcriptionally repressed in the HSC4 cells, while the KRT13 promoter was hypermethylated in all of the three OSCC cell lines. ChIP analysis revealed that PRC2-mediated trimethylation of Lys 27 on histone H3 (H3K27me3) was increased in the KRT13 promoter in the HSC3 and SAS cells. Finally, we demonstrated that the treatment of SAS cells with DZNep reactivated the transcription of KRT13 gene. Conclusions Our data provide mechanistic insights into the epigenetic silencing of KRT13 genes in OSCC cells and might be useful for the development of diagnostic markers and novel therapeutic approaches against OSCCs.