Fibroblast growth factor 2 and estrogen control the balance of histone 3 modifications targeting MAGE-A3 in pituitary neoplasia.

Abstract

PURPOSE:

Four members of the fibroblast growth factor receptor (FGFR) family transduce signals of a diverse group of FGF ligands. The FGFR2-IIIb isoform is abundantly present in the normal pituitary gland with contrasting down-regulation in neoplastic pituitary cells. cDNA profiling identified the cancer-testis antigen melanoma-associated antigen A3 (MAGE-A3) as a putative target negatively regulated by FGFR2.

EXPERIMENTAL DESIGN:

Comparisons were made between normal and neoplastic human and mouse pituitary cells. Gene expression was examined by reverse transcription-PCR, DNA methylation was determined by methylation-specific PCR and combined bisulfite restriction analysis, and histone modification marks were identified by chromatin immunoprecipitation.

RESULTS:

Normal human pituitary tissue that expresses FGFR2-IIIb does not express MAGE-A3; in contrast, pituitary tumors that are FGFR2 negative show abundant MAGE-A3 mRNA expression. MAGE-A3 expression correlates with the presence and extent of DNA promoter methylation; more frequent and higher-degree methylation is present in the normal gland compared with pituitary tumors. Conversely, pituitary tumors are hypomethylated, particularly in females where MAGE-A3 expression is nearly thrice higher than in males. Estradiol treatment induces MAGE-A3 through enhanced histone 3 acetylation and diminished methylation. The effects of estradiol are directly opposed by FGF7/FGFR2-IIIb. Down-regulation of MAGE-A3 results in p53 transcriptional induction, also through reciprocal histone acetylation and methylation modifications.

CONCLUSIONS:

These findings highlight MAGE-A3 as a target of FGFR2-IIIb and estrogen action and provide evidence for a common histone-modifying network in the control of the balance between opposing signals.

• Authors: Xuegong Zhu, Sylvia L Asa, Shereen Ezzat
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 7 Pg. 1984-96 (Apr 01 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18381936 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Estrogens
• Histones
• MAGEA3 protein, human
• Neoplasm Proteins
• RNA, Messenger
• Fibroblast Growth Factor 2

Topics

• Animals
• Antigens, Neoplasm (genetics, metabolism)
• Blotting, Western
• Cell Proliferation
• DNA Methylation
• Estrogens (metabolism)
• Female
• Fibroblast Growth Factor 2 (metabolism)
• Gene Expression
• Gene Expression Regulation, Neoplastic
• Histones (genetics)
• Humans
• Immunohistochemistry
• Immunoprecipitation
• Male
• Mice
• Neoplasm Proteins (genetics, metabolism)
• Oligonucleotide Array Sequence Analysis
• Pituitary Neoplasms (genetics, metabolism)
• RNA, Messenger (analysis)
• Reverse Transcriptase Polymerase Chain Reaction