HPV18E6 and CDK5 virus-host interaction is a prospective therapeutic target for HPV-positive cervical cancer
Year: 2026
Type: article
Abstract: 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. • CDK5 is one of the key hosts interacting partner of HPV 18E6, particularly contributing to 18E6-promoted cancer progression. • Inhibition of CDK5 using CP681301 does not only destabilizes E6, but also rescues functionality of p53, reverting the oncogenic phenotypes of HPV-positive cancer cells. • CP691301 treatment induces destabilization of E6 in a proteasome-dependent manner, thereby restoring p53.
Source: Tumour Virus Research
Authors: Chuanyun Xiao, Lixin Wang, Chichao Xia, Paul Kay Sheung Chan, Siaw Shi Boon
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,110
Funder: University Grants Committee
OpenAlex ID: W7128049742