Glucocorticoid Receptor Regulates and Interacts with LEDGF/p75 to Promote Docetaxel Resistance in Prostate Cancer Cells

Abstract

Patients with advanced prostate cancer (PCa) invariably develop resistance to anti-androgen therapy and taxane-based chemotherapy. Glucocorticoid receptor (GR) has been implicated in PCa therapy resistance; however, the mechanisms underlying GR-mediated chemoresistance remain unclear. Lens epithelium-derived growth factor p75 (LEDGF/p75, also known as PSIP1 and DFS70) is a glucocorticoid-induced transcription co-activator implicated in cancer chemoresistance. We investigated the contribution of the GR–LEDGF/p75 axis to docetaxel (DTX)-resistance in PCa cells. GR silencing in DTX-sensitive and -resistant PCa cells decreased LEDGF/p75 expression, and GR upregulation in enzalutamide-resistant cells correlated with increased LEDGF/p75 expression. ChIP-sequencing revealed GR binding sites in the LEDGF/p75 promoter. STRING protein–protein interaction analysis indicated that GR and LEDGF/p75 belong to the same transcriptional network, and immunochemical studies demonstrated their co-immunoprecipitation and co-localization in DTX-resistant cells. The GR modulators exicorilant and relacorilant increased the sensitivity of chemoresistant PCa cells to DTX-induced cell death, and this effect was more pronounced upon LEDGF/p75 silencing. RNA-sequencing of DTX-resistant cells with GR or LEDGF/p75 knockdown revealed a transcriptomic overlap targeting signaling pathways associated with cell survival and proliferation, cancer, and therapy resistance. These studies implicate the GR–LEDGF/p75 axis in PCa therapy resistance and provide a pre-clinical rationale for developing novel therapeutic strategies for advanced PCa.

Unlocking the role of non-coding RNAs in prostate cancer progression: exploring the interplay with the Wnt signaling pathway

“…Additionally, HOTTIP, a known oncogene, is upregulated in patients with PCa and PCa cell lines, promoting PCa cell proliferation and reducing sensitivity to cisplatin by activating the Wnt signaling pathway ( Jiang et al, 2019 ). As a member of a class of chemotherapy drugs known as taxanes, docetaxel acts by disrupting microtubule dynamics, ultimately inhibiting cell division and inducing cell death ( Sanchez-Hernandez et al, 2023 ). Docetaxel exerts its anti-cancer effects by targeting rapidly dividing cancer cells, inhibiting tumor growth, and promoting cancer cell death ( Sanchez-Hernandez et al, 2023 ).…”

“…As a member of a class of chemotherapy drugs known as taxanes, docetaxel acts by disrupting microtubule dynamics, ultimately inhibiting cell division and inducing cell death ( Sanchez-Hernandez et al, 2023 ). Docetaxel exerts its anti-cancer effects by targeting rapidly dividing cancer cells, inhibiting tumor growth, and promoting cancer cell death ( Sanchez-Hernandez et al, 2023 ). In the treatment of PCa, docetaxel is particularly effective in advanced or metastatic CRPC ( Gebrael et al, 2023 ).…”