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Loss of expression of the growth inhibitory gene GADD45γ, in human pituitary adenomas, is associated with CpG island methylation

Oncogene volume 23, pages 936–944 (2004)Cite this article

Abstract

Inappropriate expression of cell-cycle regulatory genes and/or their protein products are a frequent finding in pituitary tumours; however, genetic changes associated with or responsible for their dysregulation are in general uncommon. In a search for novel genes, and employing cDNA-representational difference analysis, the gene encoding GADD45γ was recently isolated and identified as being under-represented in pituitary adenomas. GADD45γ is a member of a family of genes that are induced by DNA damage and function in the negative regulation of cell growth. In this study, we further confirm this initial report that the majority of pituitary adenomas (22 of 33; 67%) do not express GADD45γ as determined by RT–PCR analysis. Loss of expression was not associated with either loss of heterozygosity or mutations within the coding region of this gene. In marked contrast, epigenetic change, namely methylation of the GADD45γ genes CpG island, was a frequent finding (19 of 33 adenoma; 58%) and was significantly associated with tumours in which GADD45γ transcript was not expressed (18 of 22; 82%; P=0.002). In common with the primary tumours, methylation-associated gene silencing of the GADD45γ gene was also found in the pituitary tumour cell line AtT20. The treatment of AtT20 cells with the demethylating agent, 5-Aza-2′-deoxycytidine, induced the re-expression of this gene. These findings show that silencing of the GADD45γ gene in pituitary tumours is primarily associated with methylation of the genes CpG island. Methylation has functional importance since reversal of this epigenetic change in a pituitary-derived cell line is associated with re-expression. Silencing of GADD45γ, a negative regulator of cell growth, is most likely responsible for conferring a selective growth advantage during tumour evolution and outgrowth.

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  1. School of Medicine, Keele University, North Staffordshire Hospital, Stoke-on-Trent, Staffordshire, ST4 7QB, UK

    Adil Bahar, John E Bicknell, David J Simpson, Richard N Clayton & William E Farrell

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  1. Adil Bahar
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Correspondence to William E Farrell.

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Bahar, A., Bicknell, J., Simpson, D. et al. Loss of expression of the growth inhibitory gene GADD45γ, in human pituitary adenomas, is associated with CpG island methylation. Oncogene 23, 936–944 (2004). https://doi.org/10.1038/sj.onc.1207193

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