The deubiquitinase USP28 maintains the expression of the transcription factor MYCN and is essential in neuroblastoma cells

Junjun Li; Jin Peng; Lingzhi Wu; Xiang Shen; Xinghua Zhen; Yimao Zhang; Huailu Ma; Yongfeng Xu; Qunli Xiong; Qing Zhu; Pumin Zhang

doi:10.1016/j.jbc.2023.104856

The deubiquitinase USP28 maintains the expression of the transcription factor MYCN and is essential in neuroblastoma cells

J Biol Chem. 2023 Jul;299(7):104856. doi: 10.1016/j.jbc.2023.104856. Epub 2023 May 23.

Authors

Junjun Li¹, Jin Peng², Lingzhi Wu², Xiang Shen³, Xinghua Zhen², Yimao Zhang⁴, Huailu Ma⁵, Yongfeng Xu⁶, Qunli Xiong⁶, Qing Zhu⁷, Pumin Zhang⁸

Affiliations

¹ Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China.
² Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
³ Chaser Therapeutics Inc., Hangzhou, Zhejiang, China.
⁴ Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu, China.
⁵ Institute of Translational Medicine, Zhejiang University Medical School, Hangzhou, Zhejiang, China.
⁶ Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China.
⁷ Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China. Electronic address: newzhuqing1972@163.com.
⁸ Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Institute of Translational Medicine, Zhejiang University Medical School, Hangzhou, Zhejiang, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: pzhangbcm@zju.edu.cn.

Abstract

Neuroblastoma (NB) is one of the most common extracranial solid tumors in children. MYCN gene amplification is highly associated with poor prognosis in high-risk NB patients. In non-MYCN-amplified high-risk NB patients, the expression of c-MYC (MYCC) and its target genes is highly elevated. USP28 as a deubiquitinase is known to regulate the stability of MYCC. We show here USP28 also regulates the stability of MYCN. Genetic depletion or pharmacologic inhibition of the deubiquitinase strongly destabilizes MYCN and stops the growth of NB cells that overexpress MYCN. In addition, MYCC could be similarly destabilized in non-MYCN NB cells by compromising USP28 function. Our results strongly suggest USP28 as a therapeutic target for NB with or without MYCN amplification/overexpression.

Keywords: MYCN; USP28; deubiquitination; neuroblastoma; ubiquitin.

Publication types

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

MeSH terms

Cell Line, Tumor
Child
Deubiquitinating Enzymes / metabolism
Gene Expression Regulation, Neoplastic
Humans
N-Myc Proto-Oncogene Protein / genetics
N-Myc Proto-Oncogene Protein / metabolism
N-Myc Proto-Oncogene Protein / therapeutic use
Neural Stem Cells* / metabolism
Neuroblastoma* / pathology
Transcription Factors / metabolism
Ubiquitin Thiolesterase / metabolism

Substances

Deubiquitinating Enzymes
N-Myc Proto-Oncogene Protein
Transcription Factors
Ubiquitin Thiolesterase
USP28 protein, human
MYCN protein, human