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USP4 Function and Multifaceted Roles in Cancer: a Possible and Potential Therapeutic Target Yizhi Wang, Li Zhou, Jun Lu, Bolun Jiang, Chengxi Liu and Junchao Guo*

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USP4 Function and Multifaceted Roles in Cancer: a Possible and Potential Therapeutic Target Yizhi Wang, Li Zhou, Jun Lu, Bolun Jiang, Chengxi Liu and Junchao Guo* Wang et al. Cancer Cell Int (2020) 20:298 https://doi.org/10.1186/s12935-020-01391-9 Cancer Cell International REVIEW Open Access USP4 function and multifaceted roles in cancer: a possible and potential therapeutic target Yizhi Wang, Li Zhou, Jun Lu, Bolun Jiang, Chengxi Liu and Junchao Guo* Abstract Cancer remains one of the major culprits causing disease-related deaths and leads to a high morbidity and similar mortality. Insidious onset, difcult early detection and a lack of broad-spectrum and efective multi-cancer therapeu- tic targets have limited the prolongation of cancer patients’ survival for decades. Therefore, a versatile therapeutic target which is involved in various cancer-related signaling pathways and diferent cancers may be more efective for cancer targeted therapy. USP4, one of the DUBs members which participates in deubiquitination, an inverse process of ubiquitination, can regulate various classical cancer-related signaling pathways, and thereby plays a vital role in some pathological and physiological processes including tumor initiation and progression. Recently, USP4 has been found to exert versatile infuences on cells proliferation, migration and invasion, also apoptosis of various tumors. Moreover, USP4 can also act as a prognostic biomarker in several cancers. This review will give a comprehensive intro- duction of USP4 about its regulatory mechanisms, related signaling pathways, pathophysiological functions and the roles in various cancers which may help us better understand its biological functions and improve future studies to construct suitable USP4-targeted cancer therapy system. Keywords: USP4, Post-translational modifcation, Cancer, Mechanisms, Therapeutic target Background drugs may cause tumor refractory and recurrence, espe- Te morbidity of cancer has been increasing recent years cially in lung cancer and pancreatic cancer, which can with the improvement of life quality and life expectancy. lead to a higher mortality [4, 5]. Radical surgery is an It is estimated that people sufering from cancers will ideal therapy for cancer control, however, limited patients increase to over 29.5 million globally by 2040 [1]. Te are suitable for it. And existing targeted therapies are too occurrence of cancers can cause great fnancial burden hard to obtain satisfactory results [6, 7]. Terefore, novel and psychologic stress to both individuals and the whole therapeutic targets are urgently needed to broaden future society due to various factors, such as lower income, methods of cancer treatment. unemployment and the time-consuming and inefciency Post-translational modifcations (PTMs) play various adjuvant and palliative therapy, especially to younger and roles in proteins expression and function modulation socioeconomically disadvantaged patients [2, 3]. Insidi- without changing mRNAs expression level or even total ous onset, early metastasis and scarce efective targeted proteins expression level which mainly include phospho- rylation, SUMOylation, glycosylation, ubiquitination, acetylation and some uncommon PTMs such as lipida- *Correspondence: [email protected] tion, citrullination [8–14]. PTMs are involved in vari- Department of General Surgery, Peking Union Medical College Hospital, ous physiological and pathological processes including Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China cancers due to countless targeted proteins. Terefore, © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://crea- tivecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdo- main/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Wang et al. Cancer Cell Int (2020) 20:298 Page 2 of 13 proteins possessing PTMs capacity have always been And the cancer target potential and clinical application deemed as potential and promising therapeutic targets value of USP4 may be underestimated. Terefore, the for cancer treatment [15, 16]. present review will give a comprehensive overview about Ubiquitination, a member of PTMs, can regulate pro- its regulatory mechanisms, involved signaling pathways, teins expression and function through attaching ubiqui- roles in pathological and physiological process, especially tin, a 76aa-protein, to the targeted proteins through the in diferent cancers to raise further studies of USP4 in sequential activation of the ubiquitin-activating enzyme, extensive cancer therapy and clinical application. ubiquitin-conjugating enzyme and ubiquitin ligase which lead to either their stabilization or inactivation, then deg- Regulatory mechanisms of USP4 protein function radation through proteasomal pathway [17, 18]. Ubiqui- Baker et al. confrmed that USP4 was a nucleocytoplas- tination is a complicated process which requires several mic shuttling protein which can locate both in the cyto- components to participate jointly. Terefore, mistakes plasm and nucleus. However, the accumulation of USP4 in any part can result in failure of ubiquitination accom- expression in the cytoplasm and nucleus varies among plishment which can be used as therapeutic targets for diferent cell types [27]. USP4 phosphorylation is an diseases treatment [19]. indispensable process leading to the localization of USP4 Deubiquitination is the inverse process of ubiquitina- from nucleus to cytoplasm. Phosphorylated USP4 was tion which is mediated by deubiquitylating enzymes found in cytoplasm and cell membrane in breast cancer (DUBs). In the process of deubiquitination, ubiquitin can cells. Further study showed that USP4 can be phospho- be removed from the substrates and then prevent sub- rylated at its Ser 445 by activated protein kinase B (AKT) strates from stabilization or degradation which depends and bind to 14-3-3 isoforms to be exported from nucleus on the detailed deubiquitination sites [20]. DUBs con- to cytoplasm and subsequently exert its deubiquitina- sist fve subclasses, namely, metalloproteinase, ubiquitin tion capacity [28]. Moreover, AKT-mediated USP4 phos- C-terminal hydrolases, Machado–Joseph disease pro- phorylation can abolish the ubiquitination of Rheb and teins, otubain proteases and ubiquitin-specifc proteases then stabilize it, which activate the mechanistic target (USPs) [20]. USPs account for the largest proportion in of rapamycin complex 1-mediated signaling pathways, DUBs which contain nearly 70 members in human spe- thus infuenced tumor growth [29]. In addition, cyclin- cies [21]. Te main function of USPs is to cleave linear dependent kinases (CDKs) were also involved in USP4 and/or branched ubiquitin precursor from monoubiqui- phosphorylation which can be hampered by purvalanol tinated or polyubiquitinated substrates and then stabi- A, a CDKs inhibitor. Dephosphorylation of USP4 can lize or inactivate target proteins [22]. As main members cause its nuclear accumulation which enhances its inter- of the deubiquitinase family, many studies have explored action with squamous cell carcinoma antigen recognized the role of USPs in various diseases, especially in cancer. by T cells 3 (SART3) and regulate spliceosome dynam- Due to numerous substrates of USPs, USPs can exert ics through deubiquitinating precursor RNA processing versatile functions in tumor progression, including epi- 3 [30]. And SART3 can also improve the deubiquitinated thelial–mesenchymal transition (EMT) and stemness activity of USP4 on K63-linked polyubiquitin chains of of cancer, metastasis, tumor-association microenviron- RNA-binding protein with serine-rich domain 1, and ment and DNA damage repair activity [23]. Terefore, stabilize it to form the spliceosome and activate the pre- because most USPs can positively regulate cancer pro- mRNA splicing process [31]. Besides deubiquitinating gression, many inhibitors have been developed to target polyubiquitin chains to stabilize targeted proteins, USP4 the specifc sites in USPs to hamper this process, such as was reported to inhibit the mono-ubiquitination of phos- broad-spectrum inhibitors WP1130 and PR619 [24, 25]. phor-inositide-dependent kinase 1 which enhanced its However, development of specifc and selective USPs activation to promote cell proliferation and metabolism inhibitor is difcult due to the conserved domain in [32]. In addition, USP4 can also interact with the S9/Rpn6 USPs. subunit of the proteasome and regulate its function with- Ubiquitin-specifc protease 4 (USP4), which is located out knowing the detailed mechanisms [33]. Tese studies in chromosome 3 (3p21,3), is one of the USPs family imply that the role of USP4 may be context-dependent. which can regulate various signaling pathways by deubiq- uitinating vital proteins [26]. Like other USPs, previous Regulated
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