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

Zhu, Xu-Dong; Lee, Katie; Sylvia, L.; Ezzat, Shereen

doi:10.2353/ajpath.2007.061111

Cited by 64 publications

(53 citation statements)

References 59 publications

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“…Pharmacologic methylation inhibition resulted in mainly FGFR2-IIIb reexpression with minimal impact on the IIIc isoform in pituitary cells [20]. Similar findings of FGFR2-IIIb isoform silencing have been previously noted in other neoplasms [28][29][30].…”

Section: The Melanoma Associated Antigen -3 (Mage-a3) Is a Target Of supporting

confidence: 72%

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Epigenetic Control in Pituitary Tumors

Ezzat

2008

Endocr J

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Abstract. Epigenetically-mediated gene dysregulation is a common feature associated with human pituitary tumorigenesis. The mechanisms leading to these changes, however, remain largely unknown. In this review, we examine changes responsible for DNA and histone modifications as independent, butpotentially interrlated modes of communication effecting chromatin remodeling. The dynamic properties of the enzymes involved in these reactions is highlighted. We use the fibroblast growth factor receptor 2 (FGFR2) as a model through which the p53-regulating melanoma-associated antigen (MAGE) system is governing in pituitary cells. The pathogenetic and potential therapeutic implications are discussed.

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Section: The Melanoma Associated Antigen -3 (Mage-a3) Is a Target Of supporting

confidence: 72%

“…We also observed that FGFR2-IIIb is expressed in the normal pituitary but significantly down-regulated in pituitary tumors [15]. Forced expression of FGFR2-IIIb arrests pituitary tumor cell cycle progression [20].…”

Section: Alternative Transcription Initiation and Oncogenic Fgfr4 (Ptmentioning

confidence: 58%

Epigenetic Control in Pituitary Tumors

Ezzat

2008

Endocr J

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“…Despite demethylation of this histone by TSA, maspin transcription was not stimulated by this HDAC1 inhibitor in the P4 corneal stromal cells. Demethylation of histone H3 associated with the genes for Ikaros and FGFR2 occurs upon TSA treatment of pituitary cells (Zhu et al, 2007a;Zhu et al, 2007b). In contrast to the maspin gene in corneal stromal fibroblasts, FGFR2 and Ikaros were re-expresed in pituitary cells with TSA treatment alone.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic silencing of maspin expression occurs early in the conversion of keratocytes to fibroblasts

Horswill

Narayan

Warejcka

et al. 2008

Experimental Eye Research

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Maspin, a 42 kDa non-classical serpin (serine protease inhibitor) that controls cell migration and invasion, is mainly expressed by epithelial-derived cells but is also expressed in corneal stromal keratocytes. Upon culture of stromal keratocytes in the presence of FBS, maspin is down regulated to nearly undetectable levels by passage two. DNA methylation is one of several processes that controls gene expression during cell differentiation, development, genetic imprinting, and carcinogenesis but has not been studied in corneal stromal cells. The purpose of this study was to determine whether DNA methylation of the maspin promoter and histone H3 dimethylation are involved in the mechanism of down regulation of maspin synthesis in human corneal stromal fibroblasts and myofibroblasts. Human donor corneal stroma cells were immediately placed into serum-free defined medium or cultured in the presence of FBS and passed into serum-free medium or medium containing FBS or FGF-2 to induce the fibroblast phenotype or TGF-β1 for the myofibroblast phenotype. These cell types are found in wounded corneas. The cells were used to prepare RNA for semi-quantitative or quantitative RT-PCR or to extract protein for western analysis. In addition, P4 FBS cultured fibroblasts were treated with the DNA demethylating agent, 5-aza-2′-deoxycytidine (5-Aza-dC), and the histone deacetylase inhibitor, trichostatin A (TSA). Cells with and without treatment were harvested and assayed for DNA methylation using sodium bisulfite sequencing. The methylation state of histone H3 associated with the maspin gene in the P4 fibroblast cells was determined using a ChIP assay. Freshly harvested corneal stromal cells expressed maspin but upon phenotypic differentiation, maspin mRNA and protein were dramatically down-regulated. Sodium bisulfite sequencing revealed that the maspin promoter in the freshly isolated stromal keratocytes was hypomethylated while both the P0 stromal cells and the P1 cells cultured in the presence of serum free defined medium, FGF-2 and TGF-β1 were hypermethylated. Down regulation of maspin synthesis was also associated with histone H3 dimethylation at Lysine 9. Both maspin mRNA and protein were reexpressed at low levels with 5-Aza-dC but not TSA treatment. Addition of TSA to 5-Aza-dC treated cells did not increase maspin expression. Treatment with 5-Aza-dC did not significantly alter demethylation of the maspin promoter but did demethylate histone H3. These results show maspin promoter hypermethylation and histone methylation occur with down regulation *Corresponding Author: Sally S. Twining, PhD, Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, Phone: 414-456-8431, Fax: 414-456-6510, e-mail: stwining@mcw.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of...

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“…These results were also confirmed by Bello et al (2006), who found promoter hypermethylation in the RB1, P14 (ARF), P16, and P73 genes, as well as the metalloproteinase inhibitor 3 (TIMP3), O-6-methylguanine DNA methyltransferase (MGMT), DAPK (DAPK1), THBS1, and CASP8 genes, some of which are involved in the apoptosis processes (DAPK and CASP8), DNA repair (MGMT) or have anti-angiogenic properties (THBS1). Additionally, reduced expression of the fibroblast growth factor receptor (FGFR2), a member of the FGF family with a critical role in pituitary development, in human pituitary tumors has been associated with gene promoter methylation (Zhu et al 2007). …”

Section: Hereditary Endocrine Tumorsmentioning

confidence: 99%

Epigenetic alterations in endocrine-related cancer

Rodríguez-Rodero¹,

Delgado²,

Fernández³

et al. 2014

Endocrine-Related Cancer

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Aberrant epigenetics is a hallmark of cancer, and endocrine-related tumors are no exception. Recent research has been identifying an ever-growing number of epigenetic alterations in both genomic DNA methylation and histone post-translational modification in tumors of the endocrine system. Novel microarray and ultra-deep sequencing technologies have allowed the identification of genome-wide epigenetic patterns in some tumor types such as adrenocortical, parathyroid, and breast carcinomas. However, in other cancer types, such as the multiple endocrine neoplasia syndromes and thyroid cancer, tumor information is limited to candidate genes alone. Future research should fill this gap and deepen our understanding of the functional role of these alterations in cancer, as well as defining their possible clinical uses.

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

Cited by 64 publications

References 59 publications

Epigenetic Control in Pituitary Tumors

Epigenetic Control in Pituitary Tumors

Epigenetic silencing of maspin expression occurs early in the conversion of keratocytes to fibroblasts

Epigenetic alterations in endocrine-related cancer

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