Down-regulation of CXCR4 expression by tamoxifen is associated with DNA methyltransferase 3B up-regulation in MCF-7 breast cancer cells

• Published in: Biomedicine & pharmacotherapy 2009-09, Vol.63 (8), p.586-591
• Main Authors: Kubarek, Ł, Kozłowska, A, Przybylski, M, Lianeri, M, Jagodzinski, P.P
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Breast Neoplasms - enzymology; Breast Neoplasms - genetics; Breast Neoplasms - immunology; Cell Line, Tumor; CpG Islands - drug effects; CXCR4; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA Methylation - drug effects; DNA Methyltransferase 3B; DNA methyltransferases; Down-Regulation; Female; Gene Expression Regulation, Neoplastic - drug effects; Gynecology. Andrology. Obstetrics; Humans; Internal Medicine; Mammary gland diseases; Medical Education; Medical sciences; Pharmacology. Drug treatments; Promoter Regions, Genetic - drug effects; Protein Isoforms; Receptors, CXCR4 - genetics; Receptors, CXCR4 - metabolism; RNA Interference; RNA, Messenger - metabolism; Selective Estrogen Receptor Modulators - pharmacology; Tamoxifen; Tamoxifen - pharmacology; Time Factors; Tumors; Up-Regulation
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2008.10.007

Abstract The CXCR4 chemokine receptor is a seven transmembrane G protein-coupled receptor present on the surface of various cells including cancer cells. The CXCR4 receptor contributes to the induction of several intracellular signalling pathways that enhance survival, proliferation, and migration of malignant cells. We observed that tamoxifen (Tam) reduced the CXCR4 transcript and protein levels in MCF-7 breast cancer cells. However, we did not see a Tam effect on CXCR4 transcript and protein levels in MCF-7LVMT3B cells with RNA interference-mediated knockdown of DNMT3B. We also observed that Tam significantly increased, for several hours, the expression of enzymatically active DNMT3B splice variants in MCF-7 cells. However, there was no Tam effect on these DNMT3B splice variants' expression in MCF-7LVMT3B cells. Bisulfite sequencing suggests that Tam may reduce CXCR4 expression via increased methylation of cytosine in the cytosine–guanosine (CpG) dinucleotide island of the CXCR4 promoter of MCF-7 breast cancer cells. Our findings suggest that Tam induces an increase in DNMT3B expression that is associated with the increase of CpG dinucleotide methylation in the CXCR4 promoter and significant reduction of CXCR4 gene expression in MCF-7 cells.