Castration-resistant prostate cancer (CRPC) is the final stage of prostate cancer (PCa). As the main androgen in males, testosterone, and its androgen receptor (AR) play an important role in CRPC. The enzyme that catalyzes testosterone, aromatase, can be influenced by CYP19A1 activity - thus possibly affecting both AR expression and CRPC. However, the function of CYP19A1 in CRPC remains unclear. Using data derived from public databases and clinical samples, we analyzed the expression of CYP19A1 in PCa and CRPC specimens. The effect of CYP19A1 on cell invasion and proliferation was investigated in vitro and in vivo; while its function in metabolizing testosterone was detected in vitro. The effect of BRD4 on CYP19A1 and AR was investigated by qRT-PCR and western blot; whereas the effect of JQ1 on cells was assessed based on the IC50 value. We found that CYP19A1 was downregulated in CRPC samples and cells which correlated with a decrease in CRPC cell invasion and proliferation, and an increase in AR expression. Inversely, CYP19A1 affected CRPC cell invasion and proliferation by suppressing the expression of AR which may be attributed to the metabolism of testosterone by CYP19A1. Moreover, the BRD4 inhibitor JQ1 induced the CYP19A1 expression and suppressed the AR expression. Following BRD4 knockdown, CYP19A1 showed higher expression while AR expression was decreased. Our findings demonstrated that CYP19A1 could reduce CRPC cell invasion and proliferation by targeting AR, and this process could be regulated by BRD4. CYP19A1 may be a potential therapeutic target and enhance BRD4 inhibition in treating CRPC.
Keywords: CYP19A1; JQ1; androgen; androgen receptor; bromo-domain-containing-protein 4; castration-resistant prostate cancer.
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