Activation of β-Catenin signaling and its crosstalk with estrogen and histone deacetylases in human uterine fibroids

Abstract

Context: Uterine fibroids (UF) are the most common benign tumor of the myometrium (MM) in women of reproductive age. However, the mechanism underlying the pathogenesis of UF is largely unknown. Objective: To explore the link between nuclear β-catenin and UF phenotype and β-catenin crosstalk with estrogen and histone deacetylases (HDACs). Design: Protein/RNA levels of β-catenin (CTNNB1 gene), its responsive markers cyclin D1 and c-Myc, androgen receptor (AR), p27, and class-I HDACs were measured in matched UF/MM tissues or cell populations. The effects of chemical inhibition/activation and genetic knockdown of CTNNB1 on UF phenotype were measured. The anti-UF effect of 2 HDAC inhibitors was evaluated. Main Outcome Measure: β-catenin nuclear translocation in response to β-catenin inhibition/ activation, estrogen, and HDAC inhibitors in UF cells. Results: UF tissues/cells showed significantly higher expression of nuclear β-catenin, cyclin D1, c-Myc, and HDACs 1, 2, 3, and 8 than MM. Estradiol induced β-catenin nuclear translocation and consequently its responsive genes in both MM and UF cells, while an estrogen receptor antagonist reversed this induction effect. Treatment with β-catenin or HDAC inhibitors led to dose-dependent growth inhibition, while Wnt3a treatment increased proliferation compared with control. Chemical inhibition of β-catenin decreased cyclin D1 and c-Myc expression levels, while β-catenin activation increased expression of the same markers. Genetic knockdown of CTNNB1 resulted in a marked decrease in β-catenin, cyclin D1, c-Myc, and AR expression. Treatment of UF cells with HDAC inhibitors decreased nuclear β-catenin, cyclin D1, and c-Myc expression. Moreover, HDAC inhibitors induced apoptosis of UF cells and cell cycle arrest. Conclusion: β-catenin nuclear translocation contributes to UF phenotype, and β-catenin signaling is modulated by estradiol and HDAC activity.