JMJD6 Is a Druggable Oxygenase That Regulates AR-V7 Expression in Prostate Cancer.
JMJD6 Is a Druggable Oxygenase That Regulates AR-V7 Expression in Prostate Cancer.
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DOI：
10.1158/0008-5472.can-20-1807
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发表时间：
2021-02-15
期刊：
影响因子：
11.2
通讯作者：
, SU2C/PCF International Prostate Cancer Dream Team
中科院分区：
文献类型：
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作者：
Paschalis A;Welti J;Neeb AJ;Yuan W;Figueiredo I;Pereira R;Ferreira A;Riisnaes R;Rodrigues DN;Jiménez-Vacas JM;Kim S;Uo T;Micco PD;Tumber A;Islam MS;Moesser MA;Abboud M;Kawamura A;Gurel B;Christova R;Gil VS;Buroni L;Crespo M;Miranda S;Lambros MB;Carreira S;Tunariu N;Alimonti A;Al-Lazikani B;Schofield CJ;Plymate SR;Sharp A;de Bono JS;, SU2C/PCF International Prostate Cancer Dream Team
晚期前列腺癌 (APC) 中的内分泌抵抗 (EnR) 是致命的。 EnR 可以由雄激素受体剪接变体 (AR-SV) 介导，其中 AR-V7 可以说是临床上最重要的变体。在这项研究中，我们确定了生成 AR-V7 的关键蛋白质，使用临床样本验证了我们的发现，并研究了 PC 模型中的剪接调控机制。三角测量研究确定 JMJD6 是 AR-V7 的关键调节因子，其证据是体外 EnR 对其上调，通过溴结构域抑制与 AR-V7 一起下调，以及将其鉴定为剪接体相关基因靶向 siRNA 筛选的热门结果。 JMJD6 蛋白水平随去势抵抗而增加 (p<0.001)，并与较高的 AR-V7 水平和较短的生存期相关 (p=0.048)。 JMJD6 敲除降低了 PC 细胞生长、AR-V7 水平以及 U2AF65 向 AR 前 mRNA 的募集。诱变研究表明，JMJD6 活性是 AR-V7 生成的关键，催化机制位于可药物口袋内。总而言之，这些数据突出了 APC 中 JMJD6 和 AR-V7 之间的关系，并支持进一步评估 JMJD6 作为该疾病的治疗靶点。
Endocrine resistance (EnR) in advanced prostate cancer (APC) is fatal. EnR can be mediated by androgen receptor splice variants (AR-SV), with AR-V7 arguably the most clinically important variant. In this study, we determined proteins key to generating AR-V7, validated our findings using clinical samples, and studied splicing regulatory mechanisms in PC models. Triangulation studies identified JMJD6 as a key regulator of AR-V7, as evidenced by its upregulation with in vitro EnR, its downregulation alongside AR-V7 by bromodomain inhibition, and its identification as a top hit of a targeted siRNA screen of spliceosome-related genes. JMJD6 protein levels increased (p<0.001) with castration resistance and were associated with higher AR-V7 levels and shorter survival (p=0.048). JMJD6 knockdown reduced PC cell growth, AR-V7 levels, and recruitment of U2AF65 to AR pre-mRNA. Mutagenesis studies suggested that JMJD6 activity is key to generation of AR-V7, with the catalytic machinery residing within a druggable pocket. Taken together, these data highlight the relationship between JMJD6 and AR-V7 in APC and support further evaluation of JMJD6 as a therapeutic target in this disease.