Insights Into the Properties, Biological Functions, and Regulation of USP21

Overview

Journal Front Pharmacol

Date 2022 Jul 18

PMID 35846989

Authors

Tao An

Yanting Lu

Xu Yan

Jingjing Hou

Affiliations

Soon will be listed here.

Abstract

Deubiquitylating enzymes (DUBs) antagonize ubiquitination by removing ubiquitin from their substrates. The role of DUBs in controlling various physiological and pathological processes has been extensively studied, and some members of DUBs have been identified as potential therapeutic targets in diseases ranging from tumors to neurodegeneration. Ubiquitin-specific protease 21 (USP21) is a member of the ubiquitin-specific protease family, the largest subfamily of DUBs. Although USP21 was discovered late and early research progress was slow, numerous studies in the last decade have gradually revealed the importance of USP21 in a wide variety of biological processes. In particular, the pro-carcinogenic effect of USP21 has been well elucidated in the last 2 years. In the present review, we provide a comprehensive overview of the current knowledge on USP21, including its properties, biological functions, pathophysiological roles, and cellular regulation. Limited pharmacological interventions for USP21 have also been introduced, highlighting the importance of developing novel and specific inhibitors targeting USP21.

Citing Articles

Unravelling the role of ubiquitin-specific proteases in breast carcinoma: insights into tumour progression and immune microenvironment modulation.

Yang H, Sun T, Sun Z, Wang H, Liu D, Wu D World J Surg Oncol. 2025; 23(1):60.

PMID: 39979972 PMC: 11841324. DOI: 10.1186/s12957-025-03667-8.

Chemical approaches to explore ubiquitin-like proteins.

Mousa R, Shkolnik D, Alalouf Y, Brik A RSC Chem Biol. 2025; .

PMID: 39950163 PMC: 11817102. DOI: 10.1039/d4cb00220b.

METTL3-Mediated m6A Methylation of USP21 Contributes to Hepatocellular Carcinoma Progression by Stabilizing H2BFS Through Deubiquitination.

Yao P, Li X, Chai J, Dong J, Chen Y, Zhang T Biochem Genet. 2024; .

PMID: 39680331 DOI: 10.1007/s10528-024-10992-2.

Roles of deubiquitinases in urologic cancers (Review).

Wu L, Wang J, Chai L, Chen J, Jin X Oncol Lett. 2024; 28(6):609.

PMID: 39525605 PMC: 11544529. DOI: 10.3892/ol.2024.14743.

The deubiquitinase USP44 enhances cisplatin chemosensitivity through stabilizing STUB1 to promote LRPPRC degradation in neuroblastoma.

Zeng L, Li Y, He S, Xu H, Zhang R, Chen K Neuro Oncol. 2024; 27(2):492-507.

PMID: 39215663 PMC: 11812030. DOI: 10.1093/neuonc/noae175.

References

Fatma H, Siddique H, Maurya S . The multiple faces of NANOG in cancer: a therapeutic target to chemosensitize therapy-resistant cancers. Epigenomics. 2021; 13(23):1885-1900. DOI: 10.2217/epi-2021-0228. View

Li Y, Yuan J . Role of deubiquitinating enzymes in DNA double-strand break repair. J Zhejiang Univ Sci B. 2021; 22(1):63-72. PMC: 7818009. DOI: 10.1631/jzus.B2000309. View

Guo Q, Shi D, Lin L, Li H, Wei Y, Li B . De-Ubiquitinating Enzymes USP21 Regulate MAPK1 Expression by Binding to Transcription Factor GATA3 to Regulate Tumor Growth and Cell Stemness of Gastric Cancer. Front Cell Dev Biol. 2021; 9:641981. PMC: 8005622. DOI: 10.3389/fcell.2021.641981. View

Tao L, Chen C, Song H, Piccioni M, Shi G, Li B . Deubiquitination and stabilization of IL-33 by USP21. Int J Clin Exp Pathol. 2014; 7(8):4930-7. PMC: 4152054. View

Smith T, Southan C . Sequencing, tissue distribution and chromosomal assignment of a novel ubiquitin-specific protease USP23. Biochim Biophys Acta. 2000; 1490(1-2):184-8. DOI: 10.1016/s0167-4781(99)00233-x. View

Hou P, Ma X, Zhang Q, Wu C, Liao W, Li J . USP21 deubiquitinase promotes pancreas cancer cell stemness via Wnt pathway activation. Genes Dev. 2019; 33(19-20):1361-1366. PMC: 6771391. DOI: 10.1101/gad.326314.119. View

Ashrafizadeh M, Zarrabi A, Orouei S, Saberifar S, Salami S, Hushmandi K . Recent advances and future directions in anti-tumor activity of cryptotanshinone: A mechanistic review. Phytother Res. 2021; 35(1):155-179. DOI: 10.1002/ptr.6815. View

Peng L, Hu Y, Chen D, Jiao S, Sun S . Ubiquitin specific peptidase 21 regulates interleukin-8 expression, stem-cell like property of human renal cell carcinoma. Oncotarget. 2016; 7(27):42007-42016. PMC: 5173112. DOI: 10.18632/oncotarget.9751. View

Garcia-Santisteban I, Banuelos S, Rodriguez J . A global survey of CRM1-dependent nuclear export sequences in the human deubiquitinase family. Biochem J. 2011; 441(1):209-17. DOI: 10.1042/BJ20111300. View

10.

Tang J, Luo Y, Xiao L . USP26 promotes anaplastic thyroid cancer progression by stabilizing TAZ. Cell Death Dis. 2022; 13(4):326. PMC: 8994751. DOI: 10.1038/s41419-022-04781-1. View

11.

Nakagawa T, Kajitani T, Togo S, Masuko N, Ohdan H, Hishikawa Y . Deubiquitylation of histone H2A activates transcriptional initiation via trans-histone cross-talk with H3K4 di- and trimethylation. Genes Dev. 2008; 22(1):37-49. PMC: 2151013. DOI: 10.1101/gad.1609708. View

12.

Ye Y, Akutsu M, Reyes-Turcu F, Enchev R, Wilkinson K, Komander D . Polyubiquitin binding and cross-reactivity in the USP domain deubiquitinase USP21. EMBO Rep. 2011; 12(4):350-7. PMC: 3077245. DOI: 10.1038/embor.2011.17. View

13.

Li Y, Lu Y, Wang S, Han Z, Zhu F, Ni Y . USP21 prevents the generation of T-helper-1-like Treg cells. Nat Commun. 2016; 7:13559. PMC: 5120220. DOI: 10.1038/ncomms13559. View

14.

Okuda H, Ohdan H, Nakayama M, Koseki H, Nakagawa T, Ito T . The USP21 short variant (USP21SV) lacking NES, located mostly in the nucleus in vivo, activates transcription by deubiquitylating ubH2A in vitro. PLoS One. 2013; 8(11):e79813. PMC: 3838379. DOI: 10.1371/journal.pone.0079813. View

15.

Xu G, Tan X, Wang H, Sun W, Shi Y, Burlingame S . Ubiquitin-specific peptidase 21 inhibits tumor necrosis factor alpha-induced nuclear factor kappaB activation via binding to and deubiquitinating receptor-interacting protein 1. J Biol Chem. 2009; 285(2):969-78. PMC: 2801298. DOI: 10.1074/jbc.M109.042689. View

16.

Harrigan J, Jacq X, Martin N, Jackson S . Deubiquitylating enzymes and drug discovery: emerging opportunities. Nat Rev Drug Discov. 2017; 17(1):57-78. PMC: 7097658. DOI: 10.1038/nrd.2017.152. View

17.

Sun M, Kim P . Data driven flexible backbone protein design. PLoS Comput Biol. 2017; 13(8):e1005722. PMC: 5587332. DOI: 10.1371/journal.pcbi.1005722. View

18.

Kim A, Koo J, Jin X, Kim W, Park S, Park S . Ablation of USP21 in skeletal muscle promotes oxidative fibre phenotype, inhibiting obesity and type 2 diabetes. J Cachexia Sarcopenia Muscle. 2021; 12(6):1669-1689. PMC: 8718070. DOI: 10.1002/jcsm.12777. View

19.

Yamaguchi M, Miyazaki M, Kodrasov M, Rotinsulu H, Losung F, Mangindaan R . Spongiacidin C, a pyrrole alkaloid from the marine sponge Stylissa massa, functions as a USP7 inhibitor. Bioorg Med Chem Lett. 2013; 23(13):3884-6. DOI: 10.1016/j.bmcl.2013.04.066. View

20.

Leung I, Dekel A, Shifman J, Sidhu S . Saturation scanning of ubiquitin variants reveals a common hot spot for binding to USP2 and USP21. Proc Natl Acad Sci U S A. 2016; 113(31):8705-10. PMC: 4978272. DOI: 10.1073/pnas.1524648113. View