CCAAT/Enhancer-Binding Protein α Is Epigenetically Silenced by Histone Deacetylation in Endometriosis and Promotes the Pathogenesis of Endometriosis

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 alpha (C/EBP alpha) for further functional experiments. C/EBP alpha 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/EBP alpha protein in endometriotic tissues. VPA treatment resulted in an accumulation of acetylated histones H3 and H4 in the promoter region of the C/EBP alpha gene in ECSCs. The compulsory expression of C/EBP alpha in ECSCs directed the inhibition of cell proliferation and the induction of apoptosis. C/EBP alpha 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-gamma (PPAR gamma), 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/EBP alpha 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.