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)