Abstract
Recent studies have shown that epigenetic alterations lead to oncogenic activation, thus indicating that these are therapeutic targets. Herein, we analyzed the efficacy and therapeutic potential of our developed histone lysine demethylase 1 (LSD1) inhibitor, NCL1, in castration-resistant prostate cancer (CRPC). The CRPC cell lines 22Rv1, PC3, and PCai1CS were treated with NCL1, and LSD1 expression and cell viability were assessed. The epigenetic effects and mechanisms of NCL1 were also evaluated. CRPC cells showed strong LSD1 expression, and cell viability was decreased by NCL1 in a dose-dependent manner. Chromatin immunoprecipitation analysis indicated that NCL1 induced histone H3 lysine 9 dimethylation accumulation at promoters of P21. As shown by Western blot and flow cytometry analyses, NCL1 also dose-dependently induced caspase-dependent apoptosis. The stimulation of autophagy was observed in NCL1-treated 22Rv1 cells by transmission electron microscopy and LysoTracker analysis. Furthermore, WST-8 assay revealed that the anti-tumor effect of NCL1 was reinforced when autophagy was inhibited by chloroquine in 22Rv1 cells. Combination index analysis revealed that a concurrent use of these drugs had a synergistic effect. In ex vivo analysis, castrated nude mice were injected subcutaneously with PCai1 cells and intraperitoneally with NCL1. Tumor volume was found to be reduced with no adverse effects in NCL1-treated mice compared with controls. Finally, immunohistochemical analysis using consecutive human specimens in pre- and post-androgen deprivation therapy demonstrated that LSD1 expression levels in CRPC, including neuroendocrine differentiation cases, were very high, and identical to levels observed in previously examined prostate biopsy specimens. NCL1 effectively suppressed prostate cancer growth in vitro and ex vivo without adverse events via the regulation of apoptosis and autophagy, suggesting that NCL1 is a potential therapeutic agent for CRPC.
Highlights
Prostate cancer is one of the most frequently diagnosed cancers in Western countries
We investigated the pharmacological mechanism of NCL1 using chromatin immunoprecipitation (ChIP), flow cytometry, and Western blot analyses
To determine the status of lysine demethylase 1 (LSD1) in human prostate cancer, the expression of LSD1 and Nkx3.1, a sensitive specific marker of differentiated adenocarcinoma originating from the prostate [18], was examined in human prostate biopsy specimens by immunohistochemistry and the staining intensity scored
Summary
Prostate cancer is one of the most frequently diagnosed cancers in Western countries. After showing an initial response, most patients develop progressive disease, referred to as castration-resistant prostate cancer (CRPC). AR controls the growth of the prostate gland, and much evidence from preclinical and clinical studies has shown that multiple androgen/AR signaling pathways implicated throughout the various stages of prostate cancer [6]. Recent reports have described the potential therapeutic implications of estrogen and related receptors in prostate cancer [7,8]. 20–40% of patients with CRPC have a poor clinical response to such agents, and most patients who initially respond acquire secondary resistance. Prospective trials are ongoing to develop the best biomarker strategy for identifying patients resistant to these drugs
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