TRIM28-mediated SUMOylation of ERG at K389 and its association with cell proliferation, PARP inhibitor response, and 53BP1 expression in castration-resistant prostate cancer.

Abstract

234 Background: Prostate cancer (PCa) patients with homologous recombination repair (HRR) gene mutations often show sensitivity to PARP inhibitors (PARPis), but this response is inconsistent in HRR-deficient cases. Intrinsic and acquired PARPi resistance remains a major barrier in castration-resistant PCa (CRPC) treatment, highlighting the need to clarify underlying molecular mechanisms. Methods: We first analyzed ERG expression in PARPi-resistant PCa tissues and its correlation with PARPi resistance in CRPC cells. Molecular assays were used to identify TRIM28-mediated ERG SUMOylation and its modification site (K389). The impact of ERG SUMOylation on SPOP-mediated degradation, TP53BP1 transcription, and HRR capacity was evaluated. Finally, small-molecule inhibitor (2-D08) and peptidic inhibitor (ERG K389-peptide) were used to verify the reversal of PARPi resistance by blocking ERG SUMOylation. Results: ERG was highly expressed in PARPi-resistant PCa tissues and positively correlated with CRPC cell resistance. TRIM28 mediated ERG SUMOylation at K389, which inhibited SPOP-dependent ERG degradation to enhance protein stability. This modification also suppressed TP53BP1 transcription, promoting HRR capacity and reducing PARPi sensitivity. Notably, 2-D08 or ERG K389-peptide blocked ERG SUMOylation, impaired DNA repair, and reversed PARPi resistance. Conclusions: TRIM28-mediated ERG K389 SUMOylation is a key axis driving PARPi resistance in CRPC via stabilizing ERG and enhancing HRR. This axis serves as a potential biomarker for resistance prediction and a druggable target, and combining TRIM28/ERG-targeted therapy with PARPis may improve outcomes for ERG-positive CRPC patients.