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(American Journal of Pathology. 2007;170:1618-1628.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.061111

Epigenetic Silencing through DNA and Histone Methylation of Fibroblast Growth Factor Receptor 2 in Neoplastic Pituitary Cells

Xuegong Zhu*{dagger}, Katie Lee{dagger}{ddagger}, Sylvia L. Asa{dagger}{ddagger} and Shereen Ezzat*{dagger}

From the Department of Medicine,* Mount Sinai Hospital and University of Toronto; The Ontario Cancer Institute{dagger} ; and the Department of Pathology,{ddagger} University Health Network and University of Toronto, Toronto, Ontario, Canada

Four members of the fibroblast growth factor receptor (FGFR) family of tyrosine kinases transduce signals of a diverse group of more than 23 fibroblast growth factor (FGF) ligands. Each prototypic receptor is composed of three immunoglobulin-like extracellular domains, two of which are involved in ligand binding. Alternative RNA splicing of one of two exons results in two different forms of the second half of the third immunoglobulin-like domain, the IIIb or IIIc isoforms. The contribution of each receptor and their isoforms in tumorigenesis remains unknown. In the pituitary, FGFR2 is expressed primarily as the IIIb isoform in normal adenohypophysial cells. In contrast, FGFR2 is significantly down-regulated in mouse corticotroph AtT20 tumor cells where the 5' promoter is methylated. Treatment of AtT20 cells with 5'-azacytidine resulted in FGFR2 re-expression, mainly as the FGFR2-IIIb isoform. Chromatin immunoprecipitation revealed evidence of histone methylation, but not of deacetylation, in the silencing of FGFR2 in AtT20 cells. Exposure of these cells to the cognate FGFR2-IIIb ligand FGF-7 resulted in diminished Rb phosphorylation and accumulation of p21 and p27, indicating diminished cell cycle progression. Examination of primary human pituitary adenomas revealed FGFR2 down-regulation in 52% (11 of 21) of samples and FGFR2 promoter DNA methylation in 45% (10 of 22) of samples. These data highlight the contribution from DNA and histone methylation as epigenetic mechanisms responsible for FGFR2 silencing in pituitary neoplasia.




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