HAUSP stabilizes Cdc25A and protects cervical cancer cells from DNA damage response

• Published in: Biochimica et biophysica acta. Molecular cell research 2020-12, Vol.1867 (12), p.118835-118835, Article 118835
• Main Authors: Das, Soumyadip, Chandrasekaran, Arun Pandian, Jo, Ki-Sang, Ko, Na Re, Oh, Seung Jun, Kim, Kye-Seong, Ramakrishna, Suresh
• Format: Article
• Language: English
• Subjects: Animals; cdc25 Phosphatases - genetics; CRISPR-Cas Systems; DNA Damage - genetics; Drug resistance; Drug Resistance, Neoplasm - genetics; Etoposide; Female; Flow Cytometry; Gene Expression Regulation, Neoplastic - genetics; Gene Knockout Techniques; HEK293 Cells; HeLa Cells; Heterografts; Humans; Knockout cells; Mice; Ubiquitin-Specific Peptidase 7 - genetics; Ultraviolet rays; USP7; Uterine Cervical Neoplasms - drug therapy; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - pathology
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/j.bbamcr.2020.118835

Resistance to DNA-damaging agents is one of the main reasons for the low survival of cervical cancer patients. Previous reports have suggested that the Cdc25A oncoprotein significantly affects the level of susceptibility to DNA-damaging agents, but the molecular mechanism remains unclear. In this study, we used Western blot and flow cytometry analyses to demonstrate that the deubiquitinating enzyme HAUSP stabilizes Cdc25A protein level. Furthermore, in a co-immunoprecipitation assay, we found that HAUSP interacts with and deubiquitinates Cdc25A both exogenously and endogenously. HAUSP extends the half-life of the Cdc25A protein by circumventing turnover. HAUSP knockout in HeLa cells using the CRISPR/Cas9 system caused a significant delay in Cdc25A-mediated cell cycle progression, cell migration, and colony formation and attenuated tumor progression in a mouse xenograft model. Furthermore, HAUSP-mediated stabilization of the Cdc25A protein produced enhanced resistance to DNA-damaging agents. Overall, our study suggests that targeting Cdc25A and HAUSP could be a promising combinatorial approach to halt progression and minimize antineoplastic resistance in cervical cancer. •HAUSP stabilizes Cdc25A protein level by extending its half-life.•HAUSP interacts with and deubiquitinates Cdc25A.•Depletion of HAUSP in HeLa cells lead to reduced tumor progression.•Stabilization of Cdc25A protein by HAUSP enhanced resistance to DNA-damaging agents.