CDK12 Deficiency Induces BRD4S to Promote Cancer Metastasis by Enhancing Phase Separation and Chromatin Engagement

Abstract CDK12 is frequently deleted and/or mutated in human cancers, and CDK12 inactivation is associated with aggressive phenotypes including the tendency to metastasis. Here, we showed that CDK12 deficiency induced intronic polyadenylation (IPA) usage in BRD4 to upregulate expression of the BRD4 short form (BRD4S). BRD4S demonstrated an enhanced capacity to form phase separation despite lacking the intrinsically disordered region (IDR) located in the C-terminal of full-length BRD4 (BRD4L). Oligomerization of BRD4S mediated phase separation through a base-interacting structural domain (BID). CUT&Tag and RNA-seq analyses revealed that BRD4S preferentially bound to the promoters of TGF-β signaling genes including TGFB2 and LTBP1, driving their expression. Consistently, BRD4S drove cancer cell dissemination in vitro and metastasis in vivo, which could be blocked by BET or TGF-β signaling pathway inhibitors. Overall, this study identifies IPA usage at the BRD4 gene locus induced by CDK12 deficiency as a mechanism responsible for BRD4S genesis, which represents an important mechanism driving cancer metastasis and a potential target for therapeutic intervention in CDK12-deficient cancers.