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ACS Biomaterials Science & Engineering

ACS Biomaterials Science & Engineering

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CRISPR screening identifies CDK12 as a conservative vulnerability of prostate cancer

Published:27 July 2021 DOI: 10.1038/s41419-021-04027-6 PMID: 34315855
Hanqi Lei,?Zifeng Wang,?Donggen Jiang,?Fang Liu,?Meiling Liu,?Xinxing Lei,?Yafei Yang,?Bin He,?Min Yan,?Hai Huang,?Quentin Liu,?Jun Pang

Abstract

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.

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Hydrocortisone 50-23-7 C21H30O5 944 suppliers $25.00-$15100.00
Hydrocortisone 50-23-7 C21H30O5 944 suppliers $25.00-$15100.00
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