Hypermethylation of the promoter region is associated with the loss of MEG3 gene expression in human pituitary tumors

J Clin Endocrinol Metab. 2005 Apr;90(4):2179-86. doi: 10.1210/jc.2004-1848. Epub 2005 Jan 11.


MEG3 is a human homolog of the mouse maternal imprinted gene, Gtl2. Gtl2 has been suggested to be involved in fetal and postnatal development and to function as an RNA. Recently our laboratory demonstrated that a cDNA isoform of MEG3, MEG3a, inhibits cell growth in vitro. Interestingly, MEG3 is highly expressed in the normal human pituitary. In striking contrast, no MEG3 expression was detected in human clinically nonfunctioning pituitary tumors. These data indicate that this imprinted gene may be involved in pituitary tumorigenesis. In the present study we investigated the mechanism underlying the absence of MEG3 expression in human clinically nonfunctioning pituitary tumors. No genomic abnormality was detected in the tumors examined. Instead, we found that two 5'-flanking regions, immediately in front of and approximately 1.6-2.1 kb upstream of the first exon, respectively, were hypermethylated in tumors without MEG3 expression compared with the normal pituitary. Reporter assays demonstrated that these two regions are functionally important in gene expression activation. Furthermore, treatment of human cancer cell lines with a methylation inhibitor resulted in MEG3 expression. We conclude that hypermethylation of the MEG3 regulatory region is an important mechanism associated with the loss of MEG3 expression in clinically nonfunctioning pituitary tumors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Azacitidine / analogs & derivatives*
  • Azacitidine / therapeutic use
  • Base Sequence
  • CpG Islands
  • DNA Methylation*
  • Decitabine
  • Exons
  • Humans
  • Loss of Heterozygosity
  • Molecular Sequence Data
  • Mutation
  • Pituitary Neoplasms / genetics*
  • Promoter Regions, Genetic*
  • Proteins / genetics*
  • RNA, Long Noncoding


  • MEG3 non-coding RNA, human
  • Proteins
  • RNA, Long Noncoding
  • Decitabine
  • Azacitidine