Targeting CDK9-dependent transcriptional addiction: a novel chemoprevention strategy for oral carcinogenesis via adenosine deaminase modulation.

Oncogenic dysregulation of transcription can entail defective control of gene expression and drive tumor initiation. This addiction to certain transcriptional programs provides opportunities to prevent carcinogenesis, and targeting transcriptional cyclin-dependent kinases (tCDKs) holds promise to show clinical benefit. Here, we firstly reported that transcriptional addiction existed in the process of oral mucosal carcinogenesis and high expression of CDK9 contributed to transcriptional dysregulation. CDK9 inhibition paused RNA Pol II transcription cycle to induce cell apoptosis in vitro and in vivo, effectively hampering carcinogenesis in 4-NQO-induced mouse models. Mechanically, targeting CDK9 decreased adenosine deaminase (ADA) expression and suppressed ADA activity, impacting on the enzymatic conversion of adenosine to inosine and resultantly caused cell apoptosis. Our findings indicate the important roles of the CDK9-dependent transcriptional addiction in precancerous stage of oral mucosal carcinogenesis, and come up with novel strategy to prevent malignant transformation of precancerous diseases. Model diagram for the role of CDK9-dependent transcriptional addiction in oral carcinogenesis. Transcriptional addiction is an important feature in the process of oral mucosal carcinogenesis. Targeting this CDK9-dependent transcriptional addiction induces cell apoptosis by downregulating ADA, and thereby interfering the enzymatic conversion of adenosine to inosine to hamper oral mucosal carcinogenesis.