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Prostate cancer (PCa) is the most common non-cutaneous cancer diagnosed in men and remains a significant health burden worldwide. Ionising radiation (IR) is the standard-of-care treatment for locally advanced PCa, however 20-50% of men relapse to more advanced disease. Aberrant epigenetic dysregulation of cancer DNA modulates gene expression and plays a key role in the development and progression of PCa. In particular, the imbalance of acetylation through overexpression of histone deacetylases (HDACs) can epigenetically silence genes through deacetylation. Such HDAC mediated gene silencing plays a key role in the development of resistance, therefore HDAC inhibition is an attractive therapeutic approach. We hypothed Class I HDAC inhibitor Entinostat (Ent) would induce anti-tumour effects and synergise with IR in prostate tumours.

Prostate cancer cell lines were treated with IR or Ent alone and in combination. Differentially expressed genes and enriched gene sets were analysed following RNA sequencing. PCa cell survival and levels of apoptosis were assessed via colony-forming assays and flow cytometry. The synergistic effects of Ent and IR were further investigated in vivo - human PCa cells were implanted in mouse xenograft models, with formed tumours subsequently treated with Ent, IR or Ent in combination with IR.

RNA sequencing revealed Ent targets pathways including DNA damage and cell cycle in PCa cells, with DNA repair regulators BRCA1 and RAD51 significantly downregulated in response to Ent. Ent increased the sensitivity of PCa cells to radiation in vitro, with combined Ent and IR reducing clonogenic survival and significantly increasing apoptosis versus single agent controls after 24h treatment. Ent synergised with radiotherapy in vivo, with combination treatment causing the most significant reduction in tumour growth versus vehicle controls. Both single agent and combination therapies were well tolerated in mouse models. Gene Set Enrichment Analysis (GSEA) revealed a role for p53 signalling enrichment and mTOR signalling suppression in the radiosensitisation effect on Ent in PCa cells.

Analysis of transcriptomic data identified DNA repair as being significantly repressed in response to Class I HDAC inhibition, suggesting potential for therapeutic combination with DNA-damaging IR. Ent resulted in a synergistic response to DNA damage induced by radiotherapy in vitro and in vivo, demonstrating potential to be integrated as a novel treatment strategy for PCa.