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

Diagnostic Pathology, Nov 2015

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.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

http://www.diagnosticpathology.org/content/pdf/s13000-015-0438-2.pdf

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

Chang et al. Diagnostic Pathology 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 Shih-Wen Chang 4 Wan-Ru Chao 1 Alexandra Ruan 3 Po-Hui Wang 5 Jau-Chen Lin 0 2 Chih-Ping Han 0 1 5 0 Equal contributors 1 Department of Pathology, Chung-Shan Medical University and Chung-Shan Medical University Hospital , Taichung , Taiwan 2 Department of Respiratory Therapy, Fu-Jen Catholic University , New Taipei , Taiwan 3 Keck School of Medicine of the University of Southern California , Los Angeles, CA , USA 4 Department of Surgery, School of Medicine, Chung-Shan Medical University and Chung-Shan Medical University Hospital , Taichung , Taiwan 5 Department of Obstetrics and Gynecology, School of Medicine, Chung-Shan Medical University and Chung-Shan Medical University Hospital , Taichung , Taiwan 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. Squamous cell carcinoma of uterine cervix; c-KIT proto-oncogene; CTCF repressor Background Epigenetic modifications may occur that result in changes in gene expression. Epigenomes represent an attractive therapeutic target. Current use of agents targeting epigenetic changes has become an interesting topic in cancer research. Additional evidence suggests that DNA methyltransferase inhibitors may serve as efficient chemo- and radiosensitizers in solid tumors [ 1 ]. Furthermore, tight association of DNA methylation and silencing of gene expression have been already established. Hypomethylation is the mechanism for ectopic oncogene activation whereas hypermethylation is the mechanism for tumor suppressor gene inactivation [ 2, 3 ]. In 54 cases of primary squamous cell carcinoma of uterine cervix (SCC) of uterine cervix, we recently demonstrated one case showing mutation-free, over-expression and paradoxical hypermethylation of the c-KIT proto-oncogene [ 4–6 ]. Within this afore-mentioned unusual case (no. 26), the DNA methylation ratio of the promoter near the first exon region in c-KIT (+) tumor area (26 T) was higher than that in adjacent c-KIT (−) non-tumor cervical epithelium (26 N). On the other hand, when comparing two cases with different c-KIT expression (no. 12 and no. 26), the DNA methylation ratio in the c-KIT (+) tumor area (26 T) was higher than that in another randomly selected c-KIT (−) tumor area (12 T) and adjacent c-KIT (−) nontumor cervical epithelium (12 N) [4]. However, the molecular mechanisms for this difference still remain unknown. The analysis of results from MethHC, a database of DNA methylation and mRNA expression profiles in human cancer showed that hyper-methylation in the promoter region of c-KIT proto-oncogene induced the downregulation of gene expression in most cancer tissues such as colon adenocarcinoma. Conversely, the increased DNA methylation ratio in upstream 500 bps of promoter region enhanced the expression of c-KIT proto-oncogene in uterine corpus endometrial carcinoma [ 7, 8 ]. This phenomenon is similar to our previous findings in the unusual uterine cervix carcinoma case [4]. Intriguingly, this is counter to the current understanding that aberrant DNA methylation tends to silencing of genes. Transcriptional repressor CTCF also known as 11-zinc finger protein or CCCTC-binding factor is a transcription factor in humans that is encoded by the CTCF gene [ 9 ]. Recent references demonstrated that absent or un-bound CTCF was associated with increased DNA methylation at a gene promoter in either normal or cancer cells [ 10, 11 ]. In addition, Lai et al. demonstrated that DNA methylation can activate the expression of CTCF-silenced oncogene BCL6 via blocking the binding of CTCF repressor to the first intron region [12]. Conversely, inhibition of DNA methyltransferase decreases BCL6 transcription due to the binding of CTCF to DNA in the methylation-sensitive region. Our previous studies and cumulative references suggested that increased methylation at the CpG islands, which are found 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 a case. Presentation of the hypothesis In this report, we propose a hypothesis for the “paradox” phenomenon between aberrant methylation and expression of c-KIT proto-onco (...truncated)


This is a preview of a remote PDF: http://www.diagnosticpathology.org/content/pdf/s13000-015-0438-2.pdf

Shih-Wen Chang, Wan-Ru Chao, Alexandra Ruan, Po-Hui Wang, Jau-Chen Lin, Chih-Ping Han. 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, Diagnostic Pathology, 2015, pp. 207, 10, DOI: 10.1186/s13000-015-0438-2