Cyclin-dependent kinase 9 (CDK9) promotes transcriptional elongation through RNAPII pause release. We now report that CDK9 is also essential for maintaining gene silencing at heterochromatic loci. Through a live cell drug screen with genetic confirmation, we discovered that CDK9 inhibition reactivates epigenetically silenced genes in cancer, leading to restored tumor suppressor gene expression, cell differentiation, and activation of endogenous retrovirus genes. CDK9 inhibition dephosphorylates the SWI/SNF protein BRG1, which contributes to gene reactivation. By optimization through gene expression, we developed a highly selective CDK9 inhibitor (MC180295, IC50 = 5 nM) that has broad anti-cancer activity in vitro and is effective in in vivo cancer models. Additionally, CDK9 inhibition sensitizes to the immune checkpoint inhibitor α-PD-1 in vivo, making it an excellent target for epigenetic therapy of cancer.
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| http://dx.doi.org/10.1016/j.cell.2018.09.051 | DOI Listing |
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Article Synopsis
- CDK9 plays a key role in cancer transcription and is a potential target for anti-cancer treatments, especially for blood cancers.
- Inhibition of CDK9 reduces α-tubulin protein levels and promotes its degradation due to decreased acetylation, which is vital for microtubule stability.
- The study reveals that CDK9 inhibitors downregulate the acetyltransferase ATAT1, compromising microtubule stability and highlighting a new therapeutic mechanism for CDK9 inhibitors in cancer treatment.
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