Abstract
BackgroundProstate cancer (PCa) is the most common malignant tumor in developed countries, which has seriously threatened men’s lifestyle and quality of life. The up-regulation of EZH2 is associated with advanced PCa and poor prognosis, making it a promising therapeutic target. However, the EZH2 inhibitors-based treatment is basically ineffective against PCa, which limits its clinical application.MethodsMicroarray data (GSE107779) from LNCaP cells treated with either siRNA against EZH2 or a EZH2 inhibitor EPZ6438 was analyzed by Limma R package. Western blot, real-time PCR and luciferase reporter assays were used to determine the EZH2-SOX9-TNFRSF11A axis and the activity of NF-κB signaling in PCa cells. CCK-8 assay was used to determine the viability of PCa cells following various treatments.ResultsGenetic ablation or pharmacological inhibition of EZH2 leads to feedback activation of NF-κB signaling in PCa cells. EZH2-dependent SOX9 expression regulates the activation of NF-κB signaling. TNFRSF11A, also known as receptor activator of NF-κB (RANK), is a downstream target of SOX9 in PCa cells. SOX9 recognizes two putative SOX9 response elements in the promoter region of TNFRSF11A gene to drive TNFRSF11A expression and downstream NF-κB signaling activation. Suppression of the NF-κB signaling by either TNFRSF11A silencing or BAY11-7082 treatment rendered PCa cells to EZH2 inhibitors.ConclusionCollectively, our finding reveals a EZH2-SOX9-TNFRSF11A axis in the regulation of activity of NF-κB signaling in PCa cells and suggests that a combination of EZH2 inhibitors and BAY11-7082 would be an effective approach for the treatment of PCa patients in the future.
Highlights
Prostate cancer (PCa) is the most common malignant tumor in developed countries, which has seriously threatened men’s lifestyle and quality of life
We found that inhibition of EZH2 inhibition led to feedback activation of NF-κB signaling in PCa cells and uncovered a molecular mechanism of adaptive resistance to EZH2 inhibitors in PCa
GSE107779 contains gene expression profile microarrays from LNCaP cells treated with either siRNA against EZH2 or a EZH2 inhibitor EPZ6438
Summary
Prostate cancer (PCa) is the most common malignant tumor in developed countries, which has seriously threatened men’s lifestyle and quality of life. The up-regulation of EZH2 is associated with advanced PCa and poor prognosis, making it a promising therapeutic target. Prostate cancer (PCa) is the most common malignant tumor in men in developed countries such as Europe and the United States [1]. The incidence of PCa in the United States has exceeded that of lung cancer [1]. The incidence of PCa in China is relatively low, ranking the sixth among male malignancies [2]. Jin et al Cancer Cell Int (2021) 21:191 diagnosed in an advanced stage and the therapeutic effect of advanced PCa is usually very poor. It is crucial to develop efficient treatments for advanced PCa patients
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