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

Clin Cancer Res. 2008 Apr 1;14(7):1984-96. doi: 10.1158/1078-0432.CCR-07-2003.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / 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
  • Neoplasm Proteins / metabolism*
  • Oligonucleotide Array Sequence Analysis
  • Pituitary Neoplasms / genetics
  • Pituitary Neoplasms / metabolism*
  • RNA, Messenger / analysis
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

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