A promising hypothesis of c-KIT methylation/ expression paradox in c-KIT (+) squamous cell carcinoma of uterine cervix ----- CTCF transcriptional repressor regulates c-KIT proto-oncogene expression

Abstract

We recently reported one interesting case showing mutation-free c-KIT proto-oncogene overexpression and paradoxical hypermethylation in 54 cases of primary squamous cell carcinoma of uterine cervix (SCC). However, its molecular mechanisms still remain unknown. We propose the hypothesis that increased methylation at the CpG islands on the promoter near the first exon region might interfere with the binding of CTCF repressor with c-KIT promoter that regulates c-KIT proto-oncogene expression in such case. Further studies focusing on the status of epigenetic modifications of mutation-free c-KIT (+) tumors are encouraged.

Fig. 1

The analysis of the c-KIT proto-oncogene promoter region and the prediction of CTCF binding sites. The c-KIT proto-oncogene contains a long CpG island including promoter, first exon and first region ranging from −736 bp to 1224 bp. The CpG island region contains at least three putative transcriptional repressor CTCF binding sites predicted by the CTCFBSDB 2.0 database [–15]. The methylation-specific (MS) PCR primer sets were designed to be located in the region between the first Exon and first intron by using MethPrimer software [16, 17]. The blue box indicates the putative CTCF binding sites. *1 indicates the transcription start site of c-KIT proto-oncogene