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Epigenomic silencing of the BMP-4 gene in pituitary adenomas: a potential target for epidrug-induced re-expression.

Abstract：

:Bone morphogenetic protein (BMP)-4 is a key mediator of anterior pituitary organogenesis. However, through inappropriate expression patterns, BMP-4 is also pathogenic in a pituitary adenoma subtype-specific context. In these cases, increase or decrease in BMP-4 in lactotroph- and corticotroph-derived adenomas, respectively, is consistent with a bifunction role for this protein toward either promotion or inhibition of cell proliferation and hormone secretion. To gain insight into the aberrations responsible for differential expression, we examined BMP-4 transcript and protein expression patterns in the major adenomas subtypes. BMP-4 transcript and protein are differentially expressed and show increase in the majority of prolactinomas relative to normal pituitary, whereas the majority of other adenoma subtypes show reduced expression relative to both prolactinoma and normal pituitaries. Reduced expression of BMP-4 is not associated with change in CpG island methylation status. However, histone tail modifications are apparent, as enrichment for a modification associated with silent genes, H3K27me3, and depletion of a modification associated with active genes, H3K9Ac. In pituitary cell lines, reduced BMP-4 expression is also associated with similar histone tail modifications and contemporaneous increase in CpG island methylation. In these cells, coincubation with the demethylating agent zebularine and histone deacetylase inhibitor, trichostatin A, reversed epigenetic changes and restored expression of BMP-4. These studies show that, in contrast to prolactinomas, other adenoma subtypes show reduced expression of BMP-4 where epidrug induced reexpression, alone or in combination with conventional therapies, may offer new treatment strategies.

journal_name

Endocrinology

journal_title

Endocrinology

authors

Yacqub-Usman K,Duong CV,Clayton RN,Farrell WE

doi

10.1210/en.2012-1231

subject

Has Abstract

pub_date

2012-08-01 00:00:00

pages

3603-12

issue

8

eissn

0013-7227

issn

1945-7170

pii

en.2012-1231

journal_volume

153

pub_type

杂志文章

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