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.
摘要：
探索抑制雄激素受体（AR）活性的靶标是抑制去势抵抗性前列腺癌（CRPC）发展的有效策略。组蛋白去甲基酶JMJD2A活性的上调是增加CRPC中AR表达的重要因素。根据我们的研究,我们发现JMJD2A和AR之间的结合亲和力在CRPC中增加，而AR增强子区域的AR组蛋白甲基化水平降低，而H3K27ac水平升高。进一步的研究表明，组蛋白脱甲基酶JMJD2A的过表达增加了JMJD2A和AR之间的结合亲和力，AR组蛋白甲基化水平降低，在AR增强子区域上调H3K27ac，增强AR活性。相反，击倒JMJD2A有效地逆转了这些影响。此外,在CRPC，JMJD2A表达上调，肿瘤固有免疫cGAS-STING信号通路被抑制，肿瘤微环境改变了,AR表达上调。然而,敲除JMJD2A和抑制干扰素基因的环GMP-AMP合酶/刺激因子（cGAS-STING）信号通路均逆转了这些作用。总之,我们的研究表明，在CRPC中，JMJD2A可以直接结合AR并通过其去甲基化活性激活残留的AR增强剂，从而促进AR表达。此外，JMJD2A表达上调抑制肿瘤的先天性免疫cGAS-STING信号通路,导致抗肿瘤免疫功能下降，并进一步促进AR表达。
