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

Area of Science:

• Molecular Oncology
• Cancer Biology
• Gene Regulation

Background:

• CDK12 (Cyclin-dependent kinase 12) inactivation is linked to aggressive human cancers and metastasis.
• The precise mechanisms by which CDK12 loss promotes cancer progression remain incompletely understood.

Purpose of the Study:

• To elucidate the functional consequences of CDK12 deficiency in cancer.
• To identify the molecular pathways mediating metastasis in CDK12-mutated cancers.
• To explore potential therapeutic targets for CDK12-deficient cancers.

Main Methods:

• Utilized CUT&Tag and RNA-sequencing to analyze gene expression and protein binding.
• Investigated protein-protein interactions and phase separation properties of BRD4 isoforms.
• Employed in vitro cell dissemination assays and in vivo metastasis models.

Main Results:

• CDK12 deficiency induces intronic polyadenylation (IPA) of BRD4, leading to increased expression of the BRD4 short form (BRD4S).
• BRD4S, lacking the intrinsically disordered region (IDR), exhibits enhanced phase separation via its base-interacting structural domain (BID).
• BRD4S preferentially binds to promoters of TGF-β signaling genes (e.g., TGFB2, LTBP1), driving their expression and promoting cancer cell dissemination and metastasis.
• BET or TGF-β pathway inhibitors effectively blocked BRD4S-mediated metastasis.

Conclusions:

• CDK12 loss triggers BRD4S production through IPA, a novel mechanism driving cancer metastasis.
• BRD4S-mediated activation of TGF-β signaling is a key driver of metastasis in CDK12-deficient cancers.
• Targeting BRD4S or the TGF-β pathway presents a promising therapeutic strategy for CDK12-deficient malignancies.