ABSTRACT
Epidemiological evidence suggests that elevated androgen levels and genetic variation related to the androgen receptor (AR) increase the risk of endometrial cancer (EC). However, the role of AR in EC is poorly understood. We report that two members of the histone demethylase KDM4 family act as major regulators of AR transcriptional activityin EC. In the MFE-296 cell line, KDM4B and AR upregulate c-myc expression, while in AN3CA cells KDM4A and AR downregulate p27kip1. Additionally, KDM4B expression is positively correlated with AR expression in EC cell lines with high baseline AR expression, while KDM4A and AR expression are positively correlated in low-AR cell lines. In clinical specimens, both KDM4B and KDM4A expression are significantly higher in EC tissues than that in normal endometrium. Finally, patients with alterations in AR, KDM4B, KDM4A, and c-myc have poor overall and disease-free survival rates. Together, these findings demonstrate that KDM4B and KDM4A promote EC progression by regulating AR activity.
Subject(s)
Cyclin-Dependent Kinase Inhibitor p27/genetics , Endometrial Neoplasms/pathology , Gene Expression Regulation, Neoplastic , Jumonji Domain-Containing Histone Demethylases/metabolism , Proto-Oncogene Proteins c-myc/genetics , Receptors, Androgen/genetics , Animals , Apoptosis , Blotting, Western , Case-Control Studies , Cell Movement , Cell Proliferation , Chromatin Immunoprecipitation , Cyclin-Dependent Kinase Inhibitor p27/metabolism , Disease Progression , Endometrial Neoplasms/genetics , Endometrial Neoplasms/metabolism , Endometrial Neoplasms/mortality , Endometrium/metabolism , Endometrium/pathology , Female , Flow Cytometry , Follow-Up Studies , Humans , Immunoenzyme Techniques , Immunoprecipitation , Jumonji Domain-Containing Histone Demethylases/genetics , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Middle Aged , Neoplasm Grading , Neoplasm Staging , Prognosis , Proto-Oncogene Proteins c-myc/metabolism , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Receptors, Androgen/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Survival Rate , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Saikosaponin-d (Ssd) is a triterpenoid saponin derived from Bupleurum falcatum L., which has been shown to exhibit a variety of pharmacological properties, including anti-inflammatory, antibacterial and antiviral properties. The aim of the present study was to investigate the effect of Ssd on the differentiation, maturation and function of human monocyte-derived dendritic cells (DCs) isolated from condylomata acuminata patients. The results of the present study demonstrated that Ssd reduced the differentiation of DCs, as evidenced by decreased expression levels of cluster of differentiation (CD)1a, CD80 and CD86 molecules and increased CD14 expression. Expression levels of the mannose receptor and CD32 were also significantly elevated, which was associated with enhanced fluorescein isothiocyanate-dextran endocytic activity. Furthermore, Ssd treatment promoted DC maturation by increasing the expression levels of CD40, CD83, CD80 and CD86. In addition, the function of mature DCs, including the secretion of IL-12 and the stimulation of lymphocyte proliferation, was significantly increased following Ssd administration. In conclusion, the present study indicated that Ssd exhibited immunomodulatory effects and may be a novel potent chemopreventive drug candidate for the treatment of condylomata acuminata.
