| HRA000724
(Open Access)
|
We used CRISPR screen and identified CDK12 as conservatively required for survival of PCa cells both under normal and AR antagonism stress. Suppression of CDK12 by the covalent inhibitor THZ531 led to an obvious anti-PCa effect. THZ531 downregulated AR signaling, and preferentially repressed a distinct class of CDK12-inhibition-sensitive transcripts (CDK12-ISTs), including prostate lineage-specific genes and contributing to survival processes of PCa cells. Integration of super-enhancers (SEs) landscape and CDK12-ISTs indicated a group of potential PCa oncogenes, and their downregulation may further explain the anti-PCa properties. Moreover, CDK12 inhibition strikingly synergized AR antagonists with significantly attenuated H3K27ac signal on AR targets and intensive SE-associated apoptosis pathway. |
