Cyclin-dependent kinase 1 (CDK1) in cancers: from upstream regulation to downstream substrates and therapeutic inhibitors.

Cyclin-dependent kinase 1 (CDK1) is a pivotal regulator of cell cycle progression. Mounting documents indicate the complicated roles of this kinase in various malignancies. Here, we roundly overview the regulation of CDK1 in malignancies, and find that CDK1 is widely upregulated in diverse cancers at either expression or enzymatic activity levels. Moreover, we comprehensively survey the CDK1-mediated phosphorylations involved in tumorigenesis and cancer progression. We find that CDK1 generally promotes cell proliferation and migration, as well as therapy resistance, via modifying proteins directly related to cell mitosis or programmed cell death, ubiquitin-proteasome system members, kinases, transcription factors or cofactors, and other proteins. Intriguingly, super-activation of CDK1 enhances sensitivity of cancer cells to drugs, especially microtubule-interfering agents. Finally, we summarize the investigations on therapeutic intervention of CDK1 and the problems. In conclusion, CDK1 is generally upregulated as an oncogene in various cancer types, where it promotes tumorigenesis and cancer progression via phosphorylating a vast array of proteins, but decreases chemo-resistance under some therapeutic conditions; diverse CDK1 inhibitors, most of which are ATP competitive, have been put into clinical or pre-clinical studies, but the issues of non-specificity and adverse side-effects need to be solved. This review may help to understand the roles of CDK1 in different scenarios and explore effective targeted drugs and strategies.