JMJD2A promotes the development of castration‐resistant prostate cancer by activating androgen receptor enhancer and inhibiting the cGAS‐STING pathway

Abstract Exploring targets for inhibiting androgen receptor (AR) activity is an effective strategy for suppressing the development of castration‐resistant prostate cancer (CRPC). Upregulation of histone demethylase JMJD2A activity is an important factor in increasing AR expression in CRPC. Based on our research, we found that the binding affinity between JMJD2A and AR increases in CRPC, while the level of AR histone methylation decreases and the H3K27ac level increases in the AR enhancer region. Further investigations revealed that overexpression of the histone demethylase JMJD2A increased the binding affinity between JMJD2A and AR, decreased AR histone methylation levels, upregulated H3K27ac in the AR enhancer region, and increased AR activity. Conversely, knocking down JMJD2A effectively reversed these effects. Additionally, in CRPC, JMJD2A expression was upregulated, the tumor‐intrinsic immune cGAS‐STING signaling pathway was suppressed, the tumor microenvironment was altered, and AR expression was upregulated. However, both knocking down JMJD2A and inhibiting the cyclic GMP‐AMP synthase/stimulator of interferon genes (cGAS‐STING) signaling pathway reversed these effects. In summary, our study indicates that in CRPC, JMJD2A can directly bind to AR and activate residual AR enhancers through its demethylation activity, thereby promoting AR expression. Furthermore, upregulation of JMJD2A expression inhibits the innate immune cGAS‐STING signaling pathway of the tumor, leading to a decrease in antitumor immune function, and further promoting AR expression.