CRISPR screening identifies CDK12 as a conservative vulnerability of prostate cancer.
CRISPR screening identifies CDK12 as a conservative vulnerability of prostate cancer.
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CRISPR 筛选确定 CDK12 是前列腺癌的保守脆弱性
DOI：
10.1038/s41419-021-04027-6
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发表时间：
2021-07-27
影响因子：
9
通讯作者：
Pang J
中科院分区：
文献类型：
--
作者：
Lei H;Wang Z;Jiang D;Liu F;Liu M;Lei X;Yang Y;He B;Yan M;Huang H;Liu Q;Pang J
雄激素受体（AR）信号传导抑制剂为前列腺癌（PCa）患者提供有限的生存益处，更糟糕的是，几乎没有可行的基因组病变限制了对PCa的靶向治疗。因此，更好地了解PCa的关键依赖性可能使更可行的治疗方法的困境。我们进行了激酶组规模的CRISPR/Cas9筛选，并将细胞周期蛋白依赖性激酶12（CDK 12）鉴定为PCa细胞存活所需的保守分子。共价抑制剂THZ 531抑制CDK 12产生明显的抗PCa作用。从机制上讲，THZ 531下调AR信号传导，并优先抑制一类独特的CDK 12抑制敏感性转录物（CDK 12-IST），包括前列腺谱系特异性基因，并有助于细胞存活过程。超级增强子（SE）景观和CDK 12-IST的整合表明一组潜在的PCa癌基因，进一步赋予PCa细胞对CDK 12抑制的敏感性。重要的是，THZ 531与多种AR拮抗剂显著协同。协同效应可能是由AR靶点上减弱的H3 K27 ac信号传导和强烈的SE相关凋亡途径驱动的。总之，我们强调了CDK 12作为PCa中的可药物靶点的有效性。THZ 531和AR拮抗剂的协同作用表明了PCa的潜在联合治疗。
Androgen receptor (AR) signaling inhibitors provide limited survival benefits to patients with prostate cancer (PCa), and worse, few feasible genomic lesions restrict targeted treatment to PCa. Thus, a better understanding of the critical dependencies of PCa may enable more feasible therapeutic approaches to the dilemma. We performed a kinome-scale CRISPR/Cas9 screen and identified cyclin-dependent kinase 12 (CDK12) as being conservatively required for PCa cell survival. Suppression of CDK12 by the covalent inhibitor THZ531 led to an obvious anti-PCa effect. Mechanistically, THZ531 downregulated AR signaling and preferentially repressed a distinct class of CDK12 inhibition-sensitive transcripts (CDK12-ISTs), including prostate lineage-specific genes, and contributed to cellular survival processes. Integration of the super-enhancer (SE) landscape and CDK12-ISTs indicated a group of potential PCa oncogenes, further conferring the sensitivity of PCa cells to CDK12 inhibition. Importantly, THZ531 strikingly synergized with multiple AR antagonists. The synergistic effect may be driven by attenuated H3K27ac signaling on AR targets and an intensive SE-associated apoptosis pathway. In conclusion, we highlight the validity of CDK12 as a druggable target in PCa. The synergy of THZ531 and AR antagonists suggests a potential combination therapy for PCa.