Castration-resistant prostate cancer (CRPC) is a lethal form of prostate cancer that no longer responds to androgen deprivation therapy. CRPC treatment primarily relies on chemotherapy, particularly taxanes such as docetaxel (Dtx) and cabazitaxel (Cbz). However, the development of taxane resistance remains a significant clinical challenge. Identifying novel targets to overcome resistance is critical for improving therapeutic efficacy. In this context, PRMT5 has emerged as a potential epigenetic regulator associated with cancer progression and drug resistance.

To identify epigenetic regulators of taxane resistance, Dtx- and Cbz-resistant CRPC cell lines were established and an epigenetic drug screen with a library of 150 molecules identified PRMT5 as a re-sensitizing modulator. PRMT5 inhibition was assessed for its role in overcoming taxane resistance using pharmacological inhibitors (CMP5, GSK591, HLCL61) and shRNA knockdown, followed by functional assays including cell viability, clonogenic assay, apoptosis (Annexin V / Caspase-3/7 assays) and cell cycle analysis. Western blot assessed PRMT5 substrates (H3R8me2, H4R3me2) and symmetric dimethylarginine levels. ChIP-seq and RNA-seq analyses identified PRMT5-mediated transcriptional regulation and epigenetic modifications. Patient data, including PRMT5 expression, Gleason scores and clinical outcomes were analyzed from public databases.

PRMT5 inhibition overcame resistance CRPC and restored taxane sensitivity, as demonstrated by decreased IC50 values and Combenefit synergy analysis. CMP5, GSK591 and HLCL61 emerged as the most effective PRMT5 inhibitors, reversing taxane resistance in SRB and clonogenic survival assays. PRMT5 pharmacological inhibition led to a reduction in sDMA levels and histone methylation markers (H3R8me2, H4R3me2), confirming on-target activity. Combination of docetaxel and PRMT5 inhibitor induced G2/M arrest in resistant cells, indicating restored taxane susceptibility. Importantly, PRMT5 inhibition no effects on parental cells, reinforcing its selective role in taxane resistance mechanisms. ChIP-seq analysis revealed differential PRMT5 binding sites between parental and resistant cells, while RNA-seq demonstrated significant downregulation of MYC and E2F target genes. Key regulatory factors, including CCND1, RB1, and ABL1, were identified through the integration of ChIP-seq and RNA-seq data, suggesting their potential relevance in taxane resistance.

Pharmacological inhibition of PRMT5 modulates cell cycle and transcriptional pathways, re-sensitizing resistant cells to taxane-based chemotherapy, with RNA-ChIP integration revealing key mechanisms related to cell cycle regulation. Given that PRMT5 inhibitors are already being evaluated in clinical trials, our findings further support its potential as a therapeutic target for taxane-refractory patients.