New insights into the dule roles CDK12 in human cancers: Mechanisms and interventions for cancer therapy
Wei Dai, Dong Xie, Hao Huang, Jingxuan Li, Caiyao Guo, Fuqiang Cao, Luo Yang, Chengyong Zhong, Shenglan Liu
Abstract
The dysregulation of cyclin-dependent kinase 12 (CDK12), which may result from genomic alterations or modulation by upstream effectors, is implicated in cancer oncogenesis and progression. CDK12 overexpression or activation is sufficient to induce tumor initiation, recurrence, and therapeutic resistance. However, CDK12 may also exert tumor-suppressive functions in a context-dependent manner. Therefore, caution is warranted when targeting CDK12 in future clinical trials. A comprehensive elucidation of the dual roles and underlying mechanisms of CDK12 in carcinogenesis is urgently needed to advance precision oncology. This review provides an overview of the current understanding of the dysregulation and biological roles of CDK12 in cancer. Subsequently, we systematically summarize the functions and mechanisms of the oncogenic and tumor-suppressive roles of CDK12 in different contexts. Finally, we discuss the potential of CDK12 as a novel therapeutic target and its implications in clinical oncology, offering insights into future directions for innovative cancer treatment strategies. • Dysregulation of CDK12 plays a pivotal role in various stages of cancer development and progression. • Overexpression or activation of CDK12 contributes to tumor initiation, growth, and progression, as well as drug resistance. • CDK12 performs a tumor-suppressive function in a context-dependent manner. • Pharmacological targeting of CDK12 shows potent anticancer activity in diverse pre-clinical models.