CCAAT/enhancer-binding protein α is epigenetically silenced by histone deacetylation in endometriosis and promotes the pathogenesis of endometriosis.
J Clin Endocrinol Metab
; 98(9): E1474-82, 2013 Sep.
Article
em En
| MEDLINE
| ID: mdl-23833041
ABSTRACT
CONTEXT Accumulating evidence suggests that various epigenetic aberrations play definite roles in the pathogenesis of endometriosis. OBJECTIVE:
The objective of the study was to determine the epigenetically silenced genes by histone deacetylation in endometriosis.DESIGN:
Histone deacetylase-1 target mRNAs that were up-regulated by valproic acid (VPA) treatment in endometriotic cyst stromal cells (ECSCs) were identified by a global mRNA microarray technique.RESULTS:
We identified 5 candidate genes and chose CCAAT/enhancer-binding protein α (C/EBPα) for further functional experiments. C/EBPα mRNA and protein expression is attenuated in ECSCs, and the expression was up-regulated by VPA stimulation. Immunohistochemical stainings also confirmed the decreased staining for C/EBPα protein in endometriotic tissues. VPA treatment resulted in an accumulation of acetylated histones H3 and H4 in the promoter region of the C/EBPα gene in ECSCs. The compulsory expression of C/EBPα in ECSCs directed the inhibition of cell proliferation and the induction of apoptosis. C/EBPα knockdown by small interfering RNA directed the stimulation of cell proliferation and the resistance to apoptosis in normal eutopic endometrial stromal cells. The expressions of peroxisome proliferator-activated receptor-γ (PPARγ), period homolog 2 (PER2), p53, apoptosis-inducing factor, mitochondrion-associated 1 (AIFM1), Bax, caspase-8, caspase-10, p16(INK4a), p21(Waf1/Cip1), cyclin-dependent kinase (cdk) 2, and cdk4 were down-regulated by C/EBPα knockdown.CONCLUSIONS:
Our findings suggest that an epigenetically suppressed tumor suppressor gene is involved in the pathogenesis of endometriosis by creating the proliferative, antiapoptotic, and other disease-specific characteristics of endometriosis. The results also suggest that histone deacetylase inhibitors are promising agents for the treatment of endometriosis.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doenças Ovarianas
/
Histonas
/
Células Estromais
/
Proteína alfa Estimuladora de Ligação a CCAAT
/
Endometriose
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Adult
/
Female
/
Humans
Idioma:
En
Revista:
J Clin Endocrinol Metab
Ano de publicação:
2013
Tipo de documento:
Article