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

• Published in: The journal of clinical endocrinology and metabolism 2013-09, Vol.98 (9), p.E1474-E1482
• Main Authors: Kawano, Yukie, Nasu, Kaei, Hijiya, Naoki, Tsukamoto, Yoshiyuki, Amada, Kohei, Abe, Wakana, Kai, Kentaro, Moriyama, Masatsugu, Narahara, Hisashi
• Format: Article
• Language: English
• Subjects: Acetylation; Adult; Apoptosis - drug effects; Apoptosis - physiology; Apoptosis Inducing Factor - genetics; Apoptosis Inducing Factor - metabolism; bcl-2-Associated X Protein - genetics; bcl-2-Associated X Protein - metabolism; Caspases - genetics; Caspases - metabolism; CCAAT-Enhancer-Binding Protein-alpha - genetics; CCAAT-Enhancer-Binding Protein-alpha - metabolism; Endometriosis - genetics; Endometriosis - metabolism; Epigenesis, Genetic; Female; Gene Silencing; Histones - genetics; Histones - metabolism; Humans; Ovarian Diseases - genetics; Ovarian Diseases - metabolism; Period Circadian Proteins - genetics; Period Circadian Proteins - metabolism; PPAR gamma - genetics; PPAR gamma - metabolism; Stromal Cells - drug effects; Stromal Cells - metabolism; Valproic Acid - pharmacology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2013-1608

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, p16INK4a, p21Waf1/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.