The deubiquitinase USP28 stabilizes the expression of RecQ family helicases and maintains the viability of triple negative breast cancer cells

Jiewei Wang; Yiping Dong; Huailu Ma; Lingzhi Wu; Xinghua Zhen; Lichun Tang; Jianping Jin; Suxia Han; Pumin Zhang; Jin Peng

doi:10.1016/j.jbc.2021.101443

The deubiquitinase USP28 stabilizes the expression of RecQ family helicases and maintains the viability of triple negative breast cancer cells

J Biol Chem. 2022 Jan;298(1):101443. doi: 10.1016/j.jbc.2021.101443. Epub 2021 Nov 22.

Authors

Jiewei Wang¹, Yiping Dong², Huailu Ma³, Lingzhi Wu⁴, Xinghua Zhen³, Lichun Tang⁵, Jianping Jin⁶, Suxia Han⁷, Pumin Zhang⁸, Jin Peng⁹

Affiliations

¹ Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China.
² Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
³ Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China; Institute of Translational Medicine, Zhejiang University Medical School, Hangzhou, Zhejiang, China.
⁴ Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China.
⁵ State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China.
⁶ Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China.
⁷ Department of Oncology, Xi'an Jiaotong University Medical College, The First Affiliated Hospital, Xi'an, China.
⁸ Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China; Institute of Translational Medicine, Zhejiang University Medical School, Hangzhou, Zhejiang, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China.
⁹ Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: [email protected].

Abstract

Triple-negative breast cancer (TNBC) lacks significant expression of the estrogen receptor, the progesterone receptor, and of human epidermal growth factor receptor. It is the most aggressive and malignant of all breast cancers, and for which, there are currently no effective targeted therapies. We have shown previously that the RecQ helicase family member RECQL5 is essential for the proliferation and survival of TNBC cells; however, the mechanism of its involvement in cell viability has not been shown. Here, we report that the expression of RecQ family helicases, including RECQL5, is regulated by the deubiquitinase USP28. We found using genetic depletion or a small molecule inhibitor that like RECQL5, USP28 is also essential for TNBC cells to proliferate in vitro and in vivo. Compromising the function of USP28 by shRNA knockdown or the inhibitor caused TNBC cells to arrest in S/G2 phases, concurrent with DNA-damage checkpoint activation. We further showed that the small molecule inhibitor of USP28 displayed anti-tumor activity against xenografts derived from TNBC cells. Our results suggest that USP28 could be a potential therapeutic target for triple negative breast cancer.

Keywords: RECQL5; RecQ family helicases; USP28; deubiquitinase; triple-negative breast cancer.

Publication types

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

MeSH terms

Cell Line, Tumor
Cell Proliferation
Cell Survival
Deubiquitinating Enzymes / metabolism
Humans
RecQ Helicases* / biosynthesis
RecQ Helicases* / genetics
Triple Negative Breast Neoplasms* / genetics
Triple Negative Breast Neoplasms* / metabolism
Triple Negative Breast Neoplasms* / pathology
Ubiquitin Thiolesterase / genetics

Substances

RECQL5 protein, human
USP28 protein, human
Deubiquitinating Enzymes
Ubiquitin Thiolesterase
RecQ Helicases