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

Soumyadip Das; Arun Pandian Chandrasekaran; Ki-Sang Jo; Na Re Ko; Seung Jun Oh; Kye-Seong Kim; Suresh Ramakrishna

doi:10.1016/j.bbamcr.2020.118835

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

Biochim Biophys Acta Mol Cell Res. 2020 Dec;1867(12):118835. doi: 10.1016/j.bbamcr.2020.118835. Epub 2020 Aug 27.

Authors

Soumyadip Das¹, Arun Pandian Chandrasekaran¹, Ki-Sang Jo¹, Na Re Ko², Seung Jun Oh³, Kye-Seong Kim⁴, Suresh Ramakrishna⁵

Affiliations

¹ Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea.
² Biomedical Research Center, Asan Institute for Life Sciences, Seoul, South Korea; Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
³ Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. Electronic address: sjoh@amc.seoul.kr.
⁴ Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea; College of Medicine, Hanyang University, Seoul, South Korea. Electronic address: ks66kim@hanyang.ac.kr.
⁵ Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea; College of Medicine, Hanyang University, Seoul, South Korea. Electronic address: suri28@hanyang.ac.kr.

PMID: 32860838
DOI: 10.1016/j.bbamcr.2020.118835

Abstract

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.

Keywords: Drug resistance; Etoposide; Knockout cells; USP7; Ultraviolet rays.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CRISPR-Cas Systems
DNA Damage / genetics
Drug Resistance, Neoplasm / genetics*
Female
Flow Cytometry
Gene Expression Regulation, Neoplastic / genetics
Gene Knockout Techniques
HEK293 Cells
HeLa Cells
Heterografts
Humans
Mice
Ubiquitin-Specific Peptidase 7 / genetics*
Uterine Cervical Neoplasms / drug therapy
Uterine Cervical Neoplasms / genetics*
Uterine Cervical Neoplasms / pathology
cdc25 Phosphatases / genetics*

Substances

CDC25A protein, human
cdc25 Phosphatases
USP7 protein, human
Ubiquitin-Specific Peptidase 7