Abstract Enzalutamide is widely used for advanced prostate cancer (PC), but acquired resistance drives progression and poor outcomes. To uncover therapeutic vulnerabilities associated with enzalutamide resistance, we established an enzalutamide-resistant derivative of LNCaP (EnzaR) through a dose-escalation approach. Transcriptomic profiling of EnzaR cells revealed hallmark features of resistance, including suppression of androgen response and enrichment of epithelial-mesenchymal transition (EMT), accompanied by increased invasiveness. For clinical relevance, intersecting EnzaR-upregulated genes with genes upregulated in circulating tumor cells isolated from human PC patients highlighted a central chromatin-remodeling module, nominating epigenetic control as a shared resistance axis. We therefore screened epigenetic targeting compounds and found HDAC inhibitors to be selectively effective in EnzaR but not parental cells, also sensitizing the innately resistant human PC line (MR49F) to enzalutamide. In-cell efficacy was confirmed by the increase in histone acetylation, consistent with on-target HDAC inhibition. Given this differential sensitivity, we revisited the transcriptome and found enrichment of “HDAC7 targets” with marked HDAC7 upregulation at mRNA and protein levels. shRNA-mediated HDAC7 silencing restored enzalutamide sensitivity and, by GSEA, reactivated androgen response (NES 3) while attenuating EMT, shifting toward a parental-like state; induction of core histone genes (e. g. , H2BC21, H4C8, H3C6) and HAT components (e. g. , KAT2B, MEAF6) supported chromatin relaxation and transcriptional reactivation. Across patient datasets, HDAC7 expression was consistently elevated, including cases with biochemical recurrence, tumor presence, metastasis, and higher Gleason scores. Moreover, higher HDAC7 levels correlated with shorter progression-free and disease-free survival. These findings highlight HDAC7 as a clinically relevant, resistance-associated factor and, to our knowledge, the first study to propose it as a novel epigenetic target to reverse enzalutamide resistance in advanced PC. Citation Format: Buse Cevatemre, Batuhan Mert. Kalkan, Ezgi Karyemez, Ipek Bulut, Hamzah Syed, David T. Miyamoto, Ceyda Acilan. Targeting HDAC7 to Overcome Enzalutamide Resistance in Prostate Cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (2Suppl): Abstract nr B009.
Cevatemre et al. (Tue,) studied this question.