Epigenetic modification of
chromatin is involved in non-malignant pituitary
neoplasia by causing abnormal expression of
tumor suppressors and oncogenes. These changes are potentially reversible, suggesting the possibility of targeting
tumor cells by restoring the expression of epigenetically silenced
tumor suppressors. The role of the
histone deacetylase (HDAC) family in pituitary
tumorigenesis is not known. We report that HDAC2 and 3, Class I HDAC members, are highly expressed in clinically non-functioning
pituitary adenomas (NFPAs) compared to normal pituitary (NP) samples as determined by RT-PCR and immunohistochemical staining (IHC). Treatment of a human NFPA derived folliculostellate cell line, PDFS, with the HDAC3 inhibitor
RGFP966 for 96 hours resulted in inhibition of cell proliferation by 70%. Furthermore, the combination of
RGFP966 with a
methyltransferase/DNMT inhibitor, 5'-aza-2'-deoxycytidine, led to the restoration of the expression of several tumor suppressor genes, including STAT1, P16, PTEN, and the large
non-coding RNA tumor suppressor MEG3, in PDFS cells. Our data support the hypothesis that both
histone modification and DNA methylation are involved in the pathogenesis of human NFPAs and suggest that targeting HDACs and DNA methylation can be incorporated into future
therapies.