HPV18E6 and CDK5 virus-host interaction is a prospective therapeutic target for HPV-positive cervical cancer

The E6 oncoprotein encoded by the cancer-causing human papillomavirus (HPV) is vital for maintaining the ability of the virus to promote cell proliferation and cancer progression. This study identified that cyclin-dependent kinase 5 (CDK5) is a previously unidentified host target of E6 encoded by cancer-causing HPV genotypes. Although E6 may not be a phosphorylation substrate of CDK5, interaction with CDK5 nonetheless increases the steady-state level of E6. To further elucidate the significance of CDK5-E6 interaction, we adopted pharmacological inhibition and silencing approaches. Leveraging the computer-aided molecular docking and in vitro screening approaches, we identified CP681301, a potent CDK5 inhibitor, which can inhibit CDK5-E6 complex formation. More intriguingly, this study underlines that CP681301 can inhibit the E6-E6AP-p53 axis, conferring inhibition on cancer phenotypes of HPV-positive cancer cells, including the ability of cells to proliferate, transform, migrate and invade through Matrigel. Our study highlights that CDK5-E6 is a promising drug target for the design of next-generation targeted therapeutics for HPV-associated diseases.