Regulation of the leucocyte chemoattractant receptor FPR in glioblastoma cells by cell differentiation.
The G protein-coupled formylpeptide receptor (FPR), known to mediate phagocytic leucocyte chemotaxis in response to bacterial- and host-derived agonists, was expressed by tumor cells in specimens of surgically removed more highly malignant human gliomas. In human glioblastoma cell lines, FPR activation increased cell motility, tumorigenicity and production of angiogenic factors. In studies of the mechanistic basis for the selective expression of FPR in more highly malignant gliomas, we found that the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (Aza), while promoting the differentiation of human glioblastoma cells, downregulated FPR expression. Aza also reduced the global methylation levels in glioblastoma cells and activated the pathway of p53 tumor suppressor. Methylation-specific polymerase chain reaction revealed that Aza treatment of tumor cells reduced the methylation of p53 promoter, which was accompanied by increased expression of p53 gene and protein. In addition, overexpression of p53 in glioblastoma cells mimicked the effect of Aza treatment as shown by increased cell differentiation but reduction in FPR expression, the capacity of tumor sphere formation in soft agar and tumorigenesis in nude mice. Furthermore, Aza treatment or overexpression of the wild-type p53 in glioblastoma cells increased the binding of p53 to FPR promoter region shown by chromatin immunoprecipitation. These results indicate that increased methylation of p53 gene retains human glioblastoma cells at a more poorly differentiated phase associated with the aberrant expression of FPR as a tumor-promoting cell surface receptor.
Huang
Jian
J
Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
Chen
Keqiang
K
Huang
Jiaqiang
J
Gong
Wanghua
W
Dunlop
Nancy M
NM
Howard
O M Zack
OM
Bian
Xiuwu
X
Gao
Yuqi
Y
Wang
Ji Ming
JM
D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002633:Chemotaxis; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D000077209:Decitabine; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008745:Methylation; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D044042:Receptors, Formyl Peptide / Q000096:biosynthesis*; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D044042:Receptors, Formyl Peptide; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine