Abstract
BackgroundDual specificity phosphatases are a class of tumor-associated proteins involved in the negative regulation of the MAP kinase pathway. Downregulation of the dual specificity phosphatase 2 (DUSP2) has been reported in cancer. Epigenetic silencing of tumor suppressor genes by abnormal promoter methylation is a frequent mechanism in oncogenesis. It has been shown that the epigenetic factor CTCF is involved in the regulation of tumor suppressor genes.MethodsWe analyzed the promoter hypermethylation of DUSP2 in human cancer, including primary Merkel cell carcinoma by bisulfite restriction analysis and pyrosequencing. Moreover we analyzed the impact of a DNA methyltransferase inhibitor (5-Aza-dC) and CTCF on the epigenetic regulation of DUSP2 by qRT-PCR, promoter assay, chromatin immuno-precipitation and methylation analysis.ResultsHere we report a significant tumor-specific hypermethylation of DUSP2 in primary Merkel cell carcinoma (p = 0.05). An increase in methylation of DUSP2 was also found in 17 out of 24 (71 %) cancer cell lines, including skin and lung cancer. Treatment of cancer cells with 5-Aza-dC induced DUSP2 expression by its promoter demethylation, Additionally we observed that CTCF induces DUSP2 expression in cell lines that exhibit silencing of DUSP2. This reactivation was accompanied by increased CTCF binding and demethylation of the DUSP2 promoter.ConclusionsOur data show that aberrant epigenetic inactivation of DUSP2 occurs in carcinogenesis and that CTCF is involved in the epigenetic regulation of DUSP2 expression.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2087-6) contains supplementary material, which is available to authorized users.
Highlights
Dual specificity phosphatases are a class of tumor-associated proteins involved in the negative regulation of the MAP kinase pathway
Decreased expression of dual specificity phosphatase 2 (DUSP2) is associated with its promoter hypermethylation To further analyze the impact of epigenetic regulation of DUSP2 in carcinogenesis we investigated its expression in normal tissues and cancer cell lines (Fig. 3)
Downregulation of the negative regulator DUSP2 of the oncogenic mitogen-activated protein kinases (MAPK) signaling pathway has been reported in cancer
Summary
Dual specificity phosphatases are a class of tumor-associated proteins involved in the negative regulation of the MAP kinase pathway. Downregulation of the dual specificity phosphatase 2 (DUSP2) has been reported in cancer. Epigenetic silencing of tumor suppressor genes by abnormal promoter methylation is a frequent mechanism in oncogenesis. Dual specificity phosphatases (DUSPs) are negative regulators of mitogen-activated protein kinases (MAPK) that regulate proliferative signaling pathways, which are often activated in cancer [1,2,3]. Epigenetic silencing of tumor suppressor genes (TSG) is one of the most relevant molecular alteration that occurs during carcinogenesis [10]. Promoter hypermethylation of TSG occurs in cancer through methylation at the DNA level at C5 of cytosine (5mC), when found as a dinucleotides with guanine. The frequency of 5hmC suggests that these modified cytosine bases play
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
