KDM4A promotes NEPC progression through regulation of MYC expression

Purpose Despite advancement in treatment, prostate cancer (PCa) remains the second leading cause of death among men. Neuroendocrine prostate cancer (NEPC) represents one of the most lethal forms of PCa and lacks life-prolonging treatment. Here we identified histone lysine demethylase KDM4A as a driver in NEPC progression and an effective therapeutic target.

Experimental Design The expression of KDM4A in human and mouse NEPC was examined by analyzing publicly available RNA-seq datasets and immunohistochemistry (IHC). KDM4A was knocked down (KD) using lentiviral RNA-interference or knocked out (KO) using CRISPR/Cas9 genome editing. Western blotting, cell proliferation, soft-agar colony formation assay, subcutaneous xenograft, RNA-seq, ChIP-seq, and small molecule inhibitors treatment in mice were used to determine the functions of KDM4A, KDM4A’s downstream signaling pathways, and the therapeutic response of KDM4 inhibitors.

Results We found that KDM4A mRNA and protein are overexpressed in human and mouse NEPC compared to adenocarcinoma. Also, we showed that knockdown or knockout of KDM4A in NEPC cell lines suppressed cancer cell growth in vitro and in vivo. Mechanistically, we found that KDM4A KD led to suppression of MYC signaling through the direct transcriptional regulation of MYC. Importantly, MYC signaling is hyper-activated in human and mouse NEPC. Furthermore, a potent pan-KDM4 inhibitor QC6352 significantly reduced NEPC cell growth in vitro and in vivo.

Conclusions We demonstrated that KDM4A drives NEPC progression through regulation of MYC and targeting KDM4A can potentially be an effective therapeutic strategy for NEPC.

Translational Relevance Neuroendocrine prostate cancer (NEPC) represents a highly lethal subtype of prostate cancer that lacks effective treatment options. Since epigenetic dysregulation is a hallmark of NEPC, we aim to identify novel epigenetic drivers in NEPC progression and test the therapeutic efficacy of epigenetic inhibitors. By combining RNA sequencing (RNA-seq) analysis of publicly available datasets and immunohistochemical validation, we identify KDM4A as a highly expressed histone lysine demethylase in NEPC. Our preclinical results using genetic and pharmacological approaches demonstrate that KDM4A plays a critical role in NEPC growth in vitro and in vivo. The present work suggests that targeting KDM4A with pan-KDM4 inhibitors is a highly effective therapeutic approach in NEPC.