A genome-wide RNA interference screen identifies new regulators of androgen receptor function in prostate cancer cells.
A genome-wide RNA interference screen identifies new regulators of androgen receptor function in prostate cancer cells.
复制标题
DOI：
10.1101/gr.144774.112
复制
发表时间：
2013-04
期刊：
影响因子：
7
通讯作者：
Garabedian MJ
中科院分区：
文献类型：
--
作者：
Imberg-Kazdan K;Ha S;Greenfield A;Poultney CS;Bonneau R;Logan SK;Garabedian MJ
雄激素受体（AR）是雄激素依赖性前列腺癌和去势抵抗性前列腺癌的介质。鉴定影响AR转录活性的细胞因子原则上可以产生降低AR活性和对抗前列腺癌的新靶点，但尚未确定AR依赖性转录活性所需基因的全面分析。使用无偏见的遗传方法，利用AR信号的进化保守性，我们已经进行了全基因组RNAi屏幕在果蝇细胞中的AR转录活性所需的基因，并将结果应用于人前列腺癌细胞。我们鉴定了45种AR调节因子，包括已知的通路组分和具有先前未与AR调节相关的功能的基因，如HIPK2（蛋白激酶）和MED19（介体复合物的亚基）。人类前列腺癌细胞中HIPK2和MED19的消耗降低了AR靶基因的表达，重要的是，降低了雄激素依赖性和去势抵抗性前列腺癌细胞的增殖。我们还系统地分析了额外的介体亚基，并发现了一小部分介体亚基，它们解释AR信号传导并影响AR依赖性转录和前列腺癌细胞增殖。重要的是，通过FDA批准的激酶抑制剂靶向HIPK2表型模拟了RNAi的耗竭效应，并减少了AR阳性而非AR阴性的治疗抗性前列腺癌细胞的生长。因此，我们的筛选已经产生了新的AR调节剂，包括减少去势抵抗性前列腺癌细胞增殖的药物靶点。
The androgen receptor (AR) is a mediator of both androgen-dependent and castration-resistant prostate cancers. Identification of cellular factors affecting AR transcriptional activity could in principle yield new targets that reduce AR activity and combat prostate cancer, yet a comprehensive analysis of the genes required for AR-dependent transcriptional activity has not been determined. Using an unbiased genetic approach that takes advantage of the evolutionary conservation of AR signaling, we have conducted a genome-wide RNAi screen in Drosophila cells for genes required for AR transcriptional activity and applied the results to human prostate cancer cells. We identified 45 AR-regulators, which include known pathway components and genes with functions not previously linked to AR regulation, such as HIPK2 (a protein kinase) and MED19 (a subunit of the Mediator complex). Depletion of HIPK2 and MED19 in human prostate cancer cells decreased AR target gene expression and, importantly, reduced the proliferation of androgen-dependent and castration-resistant prostate cancer cells. We also systematically analyzed additional Mediator subunits and uncovered a small subset of Mediator subunits that interpret AR signaling and affect AR-dependent transcription and prostate cancer cell proliferation. Importantly, targeting of HIPK2 by an FDA-approved kinase inhibitor phenocopied the effect of depletion by RNAi and reduced the growth of AR-positive, but not AR-negative, treatment-resistant prostate cancer cells. Thus, our screen has yielded new AR regulators including drugable targets that reduce the proliferation of castration-resistant prostate cancer cells.
登录
查看更多内容
影响因子：
82.9
作者：
Chen, CD;Welsbie, DS;Sawyers, CL
通讯作者：
Sawyers, CL
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
6
作者：
Comuzzi, B;Lambrinidis, L;Culig, Z
通讯作者：
Culig, Z
影响因子：
4.5
作者：
Aragon-Ching JB;Jain L;Gulley JL;Arlen PM;Wright JJ;Steinberg SM;Draper D;Venitz J;Jones E;Chen CC;Figg WD;Dahut WL
通讯作者：
Dahut WL
影响因子：
4.8
作者：
Hikasa, Hiroki;Sokol, Sergei Y.
通讯作者：
Sokol, Sergei Y.