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

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-7(LVMT3B) 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-7(LVMT3B) 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.

• Authors: Ł Kubarek, A Kozłowska, M Przybylski, M Lianeri, P P Jagodzinski
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 63 Issue 8 Pg. 586-91 (Sep 2009) ISSN: 1950-6007 [Electronic] France
• PMID: 19019622 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CXCR4 protein, human
• Protein Isoforms
• RNA, Messenger
• Receptors, CXCR4
• Selective Estrogen Receptor Modulators
• Tamoxifen
• DNA (Cytosine-5-)-Methyltransferases
• DNA methyltransferase 3B

Topics

• Breast Neoplasms (enzymology, genetics, immunology)
• Cell Line, Tumor
• CpG Islands (drug effects)
• DNA (Cytosine-5-)-Methyltransferases (genetics, metabolism)
• DNA Methylation (drug effects)
• Down-Regulation
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Promoter Regions, Genetic (drug effects)
• Protein Isoforms
• RNA Interference
• RNA, Messenger (metabolism)
• Receptors, CXCR4 (genetics, metabolism)
• Selective Estrogen Receptor Modulators (pharmacology)
• Tamoxifen (pharmacology)
• Time Factors
• Up-Regulation