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Updated: Oct 26, 2025
Virus Delivery of CRISPR Guides to the Murine Prostate for Gene Alteration
Published on: April 27, 2018
CRISPR screening identifies CDK12 as a conservative vulnerability of prostate cancer
Hanqi Lei1,2, Zifeng Wang3, Donggen Jiang1
1Department of Urology, Kidney and Urology Center, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
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.
Insights
Targeting cyclin-dependent kinase 12 (CDK12) shows promise for prostate cancer (PCa) treatment. Inhibiting CDK12 with THZ531 and combining it with AR antagonists offers a potential new therapy for PCa patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Androgen receptor (AR) signaling inhibitors offer limited survival benefits for prostate cancer (PCa).
- Limited genomic lesions in PCa restrict effective targeted treatments.
- Identifying critical PCa dependencies is crucial for developing new therapeutic strategies.
Purpose of the Study:
- To identify novel therapeutic targets and strategies for prostate cancer.
- To investigate the role of cyclin-dependent kinase 12 (CDK12) in PCa cell survival and AR signaling.
- To evaluate the efficacy of CDK12 inhibition and its combination with AR antagonists in PCa.
Main Methods:
- A kinome-scale CRISPR/Cas9 screen was employed to identify essential genes in PCa.
- The covalent inhibitor THZ531 was used to suppress CDK12 activity.
- AR signaling, CDK12-inhibition-sensitive transcripts (CDK12-ISTs), super-enhancer (SE) landscape, and H3K27ac signaling were analyzed.
- Synergistic effects of THZ531 with AR antagonists were assessed.
Main Results:
- CDK12 was identified as essential for PCa cell survival.
- THZ531 demonstrated significant anti-PCa effects by downregulating AR signaling and repressing CDK12-ISTs.
- Integration of SE landscape and CDK12-ISTs revealed potential PCa oncogenes.
- THZ531 synergized with AR antagonists, potentially via attenuated H3K27ac signaling and enhanced apoptosis.
Conclusions:
- CDK12 is a druggable target for prostate cancer therapy.
- The combination of THZ531 and AR antagonists shows significant therapeutic potential for PCa.
- Targeting CDK12 offers a novel approach to overcome limitations of current PCa treatments.
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