Deubiquitinase USP13 dictates MCL1 stability and sensitivity to BH3 mimetic inhibitors

Shengzhe Zhang; Meiying Zhang; Ying Jing; Xia Yin; Pengfei Ma; Zhenfeng Zhang; Xiaojie Wang; Wen Di; Guanglei Zhuang

doi:10.1038/s41467-017-02693-9

Deubiquitinase USP13 dictates MCL1 stability and sensitivity to BH3 mimetic inhibitors

Nat Commun. 2018 Jan 15;9(1):215. doi: 10.1038/s41467-017-02693-9.

Authors

Shengzhe Zhang^{1

2}, Meiying Zhang³, Ying Jing¹, Xia Yin³, Pengfei Ma¹, Zhenfeng Zhang⁴, Xiaojie Wang⁵, Wen Di^{1

3}, Guanglei Zhuang^{6

7}

Affiliations

¹ State Key Laboratory of Oncogenes and Related Genes, Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
² School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200240, China.
³ Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
⁴ State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China.
⁵ Department of Obstetrics and Gynecology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200050, China.
⁶ State Key Laboratory of Oncogenes and Related Genes, Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. [email protected].
⁷ Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. [email protected].

Abstract

MCL1 is a pivot member of the anti-apoptotic BCL-2 family proteins. While a distinctive feature of MCL1 resides in its efficient ubiquitination and destruction, the deubiquitinase USP9X has been implicated in the preservation of MCL1 expression by removing the polyubiquitin chains. Here we perform an unbiased siRNA screen and identify that the second deubiquitinase, USP13, regulates MCL1 stability in lung and ovarian cancer cells. Mechanistically, USP13 interacts with and stabilizes MCL1 via deubiquitination. As a result, USP13 depletion using CRISPR/Cas9 nuclease system inhibits tumor growth in xenografted nude mice. We further report that genetic or pharmacological inhibition of USP13 considerably reduces MCL1 protein abundance and significantly increases tumor cell sensitivity to BH3 mimetic inhibitors targeting BCL-2 and BCL-XL. Collectively, we nominate USP13 as a novel deubiquitinase which regulates MCL1 turnover in diverse solid tumors and propose that USP13 may be a potential therapeutic target for the treatment of various malignancies.

Publication types

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

MeSH terms

Aniline Compounds / pharmacology
Animals
Benzylamines / pharmacology
CRISPR-Cas Systems
Cell Line, Tumor
Endopeptidases / genetics
Endopeptidases / metabolism*
HEK293 Cells
Humans
Mice, Inbred BALB C
Mice, Nude
Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors
Myeloid Cell Leukemia Sequence 1 Protein / genetics
Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
Neoplasms / drug therapy
Neoplasms / genetics
Neoplasms / metabolism*
Protein Binding
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
Proto-Oncogene Proteins c-bcl-2 / metabolism
Quinazolines / pharmacology
RNA Interference
Sulfonamides / pharmacology
Ubiquitin-Specific Proteases
Ubiquitination / drug effects
Xenograft Model Antitumor Assays*
bcl-X Protein / antagonists & inhibitors
bcl-X Protein / metabolism

Substances

Aniline Compounds
Benzylamines
MCL1 protein, human
Myeloid Cell Leukemia Sequence 1 Protein
Proto-Oncogene Proteins c-bcl-2
Quinazolines
Sulfonamides
bcl-X Protein
spautin-1
Endopeptidases
USP13 protein, human
Ubiquitin-Specific Proteases
navitoclax