Epigenetic regulation of the expression of the novel stem cell marker CDCP1 in cancer cells

Abstract

CDCP1 is a novel stem cell marker that is expressed in several types of cancer. The mechanisms by which CDCP1 expression is regulated, and the clinical implications of this marker, have not been clarified. In this report, we examine the epigenetic regulation of CDCP1 expression in cell lines and clinical samples from patients with breast cancer. Many CpG sequences were localized around the transcription initiation site of CDCP1. These CpG motifs were found to be poorly methylated in cell lines with high levels of CDCP1 expression and heavily methylated in cell lines with low levels of CDCP1 expression. The in vitro methylation of CpG sites decreased CDCP1 promoter activity, and the addition of a demethylating reagent restored activity. In 25 breast cancer samples, an inverse correlation was noted between the CDCP1 expression level and the proportion of methylated to non-methylated CpG sites. Tumours with high-level CDCP1 expression showed higher levels of proliferation, as revealed by immunohistochemical detection of the MIB-1 antigen, than tumours with low-level CDCP1 expression. These findings indicate that the expression of CDCP1 is regulated by methylation of its promoter region in tumours. CDCP1 expression may prove to be useful in the further characterization of cancers.

The role of membrane microdomains in transmembrane signaling through the epithelial glycoprotein Gp140/CDCP1

“…It was also identified as CDCP1, an mRNA transcript that is up-regulated in colon and lung cancer [38], as well as skeletal muscle, colon, and various human tumor lines [39,40]. Current observations suggest that CDCP1 expression negatively correlates with the amount of methylation found at the promoter region [41], but only weakly correlates with the metatstatic potential of cell lines [39]. Further, Gp140 is regulated at the protein level through SFK-dependent phosphorylation (Zaitsevakaia et al, manuscript in preparation).…”

The cell surface glycoprotein CDCP1 in cancer—Insights, opportunities, and challenges

“…For example, as part of the initial report on the CDCP1 gene and coding sequence, elevated CDCP1 mRNA levels were detected in several solid tumors including colon, lung, and breast cancers relative to unmatched normal tissues (1). Further support for increased CDCP1 expression in breast cancer came from a study which, although providing no comparison with normal breast tissue, showed that CDCP1 mRNA levels inversely correlated with methylation of the CDCP1 transcription initiation site in all 25 breast cancer patient samples examined (12). Consistently, immunohistochemical analysis of two breast cancer samples demonstrated that a patient with high CDCP1 mRNA levels had correspondingly high CDCP1 protein levels that correlated with high expression of the proliferation marker Ki67, while a patient with low CDCP1 mRNA levels had correspondingly low CDCP1 and Ki67 protein levels (12).…”

“…Further support for increased CDCP1 expression in breast cancer came from a study which, although providing no comparison with normal breast tissue, showed that CDCP1 mRNA levels inversely correlated with methylation of the CDCP1 transcription initiation site in all 25 breast cancer patient samples examined (12). Consistently, immunohistochemical analysis of two breast cancer samples demonstrated that a patient with high CDCP1 mRNA levels had correspondingly high CDCP1 protein levels that correlated with high expression of the proliferation marker Ki67, while a patient with low CDCP1 mRNA levels had correspondingly low CDCP1 and Ki67 protein levels (12). In another small study, analysis of colon adenocarcinoma and adjacent nondiseased tissue from three patient samples indicated a potential link between more malignant colon cancer cells and CDCP1 staining intensity, although a conclusive association could not be demonstrated from such a small cohort (2).…”

“…With clear evidence of upregulation of CDCP1 in lung (1, 9) and kidney (10) cancers, and to a lesser extent in breast cancer (1,12) along with indications of dysregulated expression in colon cancer (1, 2, 11), it is likely that aberrant CDCP1 expression facilitates cancer progression in humans. Accordingly, targeting of CDCP1 in these settings may represent a rationale approach to treat certain tumors.…”

“…In two other papers aimed at identifying molecules associated with important signaling proteins, CDCP1 was identified as a protein kinase Cd (PKCd) (7) and a tetraspanin CD9 (8) interacting protein. Strengthening the proposal that CDCP1 has a role in cancer progression, dysregulated CDCP1 expression has been associated with cancer of the lung (1,9), kidney (10), colon (1,2,11), and breast (1,12). In addition, CDCP1 has been suggested as an independent marker for leukemia (13).…”