JMJD2A participates in cytoskeletal remodeling to regulate castration-resistant prostate cancer docetaxel resistance

Abstract

Abstract Background To investigate underlying mechanism of JMJD2A in regulating cytoskeleton remodeling in castration-resistant prostate cancer (CRPC) resistant to docetaxel. Methods Tissue samples from CRPC patients were collected, and the expression of JMJD2A, miR-34a and cytoskeleton remodeling-related proteins were evaluated by qPCR, western blot and immunohistochemistry, and pathological changes were observed by H&E staining. Further, JMJD2A, STMN1 and TUBB3 were knocked down using shRNA in CRPC cell lines, and cell viability, apoptosis and western blot assays were performed. The interaction between miR-34a/STMN1/β3-Tubulin was analyzed with dual-luciferase reporter and co-immunoprecipitation assays. Results In clinical experiment, the CRPC-resistant group showed higher expression of JMJD2A, STMN1, α-Tubulin, β-Tubulin and F-actin, and lower expression of miR-34a and β3-Tubulin compared to the sensitive group. In vitro experiments showed that JMJD2A could regulate cytoskeletal remodeling through the miR-34a/STMN1/β3-Tubulin axis. The expression of miR-34a was elevated after knocking down JMJD2A, and miR-34a targeted STMN1. The overexpression of miR-34a was associated with a decreased expression of STMN1 and elevated expression of β3-Tubulin, which led to the disruption of the microtubule network, decreased cancer cell proliferation, cell cycle arrest in the G0/G1 phase, and increased apoptosis. Conclusion JMJD2A promoted docetaxel resistance in prostate cancer cells by regulating cytoskeleton remodeling through the miR-34a/STMN1/β3-Tubulin axis.

Keywords

• Castration-resistant prostate cancer
• Docetaxel resistance
• JMJD2A
• miR-34a/STMN1/β3-Tubulin
• PDX animal model