KDM7A and KDM1A inhibition suppresses tumour promoting pathways in prostate cancer.

Treatment resistance has become a major challenge in cancer research, particularly for patients with advanced castration resistant prostate cancer (CRPC) where no curative therapies are available. Epigenetic alterations play a significant role in cancer progression. In prostate cancer (PCa), where androgen receptor (AR) is the primary oncogenic driver, epigenetic coregulators, specifically lysine demethylases (KDMs), have previously been identified as factors that alter the transcriptome as cancer cells acquire resistance. KDM7A has been identified as a cancer-promoting factor in many cancers; however, its role in PCa remains largely unexplored. This study investigates the clinical relevance of KDM7A in comparison with the well-studied KDM1A in PCa. Using PCa cell line models, we confirm KDM7A as an AR coregulator. By exploiting commercially available pharmacological inhibitors, we demonstrate that in AR-positive CRPC cell lines, combinatory inhibition of KDM1A and KDM7A leads to a loss of AR and the AR-driven transcriptome, which in turn attenuates cancer-promoting cell phenotypes. These findings highlight the potential of combination-targeted therapies in tackling advanced prostate cancers.