Ubiquitin-specific protease 28: the decipherment of its dual roles in cancer development

Abstract

As significant posttranslational modifications, ubiquitination and deubiquitination, whose balance is modulated by ubiquitin-conjugating enzymes and deubiquitinating enzymes (DUBs), can regulate many biological processes, such as controlling cell cycle progression, signal transduction and transcriptional regulation. Belonging to DUBs, ubiquitin-specific protease 28 (USP28) plays an essential role in turning over ubiquitination and then contributing to the stabilization of quantities of substrates, including several cancer-related proteins. In previous studies, USP28 has been demonstrated to participate in the progression of various cancers. Nevertheless, several reports have recently shown that in addition to promoting cancers, USP28 can also play an oncostatic role in some cancers. In this review, we summarize the correlation between USP28 and tumor behaviors. We initially give a brief introduction of the structure and related biological functions of USP28, and we then introduce some concrete substrates of USP28 and the underlying molecular mechanisms. In addition, the regulation of the actions and expression of USP28 is also discussed. Moreover, we concentrate on the impacts of USP28 on diverse hallmarks of cancer and discuss whether USP28 can accelerate or inhibit tumor progression. Furthermore, clinical relevance, including impacting clinical prognosis, influencing therapy resistance and being the therapy target in some cancers, is depicted systematically. Thus, assistance may be given to future experimental designs by the information provided here, and the potential of targeting USP28 for cancer therapy is emphasized.

Keywords: Biomarker; Cancer; Prognosis; Therapy resistance; USP28.

Fig. 1

Structures of USP28 and USP25. Both of USP28 and USP25 possess the N-terminal domain, the catalytic “conserved” USP domain and the C-terminal extension domain and the identity of the three domains between USP28 and USP25 is 40%, 57% and 48% respectively. Except for the shared domains including one UBA, one SIM and one UIM, the N-terminal of USP25 has another more UIM compared to USP28. Domains including UBA and UIM compose of UBR, which is responsible for ubiquitin recognition. As for SIM, USP28's SIM prefers to interact with SUMO-1/2 while USP25's prefers to interact with SUMO-2/3. SIM SUMO-interaction motif, UBA ubiquitin-associated domain, UBR ubiquitin-binding region, UIM ubiquitin-interaction motif, USP ubiquitin-specific protease

Fig. 2

Schematic introduction of ubiquitination and deubiquitination. Sequential catalyzation caused by E1, E2 and E3 contributes to ubiquitin activation, ubiquitin conjugation and ubiquitin ligation respectively, leading to the ubiquitination of substrates. Ubiquitination of substrates results in the proteasomal degradation of themselves. While if deubiquitinases such as USP28 exist, the ubiquitin chains of substrates can be removed and the interaction between the enzyme and the substrates is realized directly or indirectly (with the help of E3 ligases)

Fig. 3

Regulatory mechanisms of the stability, activation and expression of USP28. During the expression of USP28, both Tet1 and c-Jun can function on USP28 promoter and contribute to the enhancement of USP28 transcription. While miRNAs involving miR-363-3p which can be inhibited by USP28 substrate MYC, miR-500a-5p and miR-3940-5p have the capacity to interact with USP28 mRNA and then inhibit the translation of USP28. SUMOylation and LDHA can respectively suppresses and promotes the activation of USP28, and the former one can be antagonized by SENP1. Moreover, USP28 substrate HIF-1α can induce SENP1, thus forming a feedback loop. Besides, ubiquitination and caspase-8 can induce the destabilization of USP28, and HDAC5 brings about the inhibition of USP28 ubiquitination. ATG7 autophagy related protein 7, AUF1 ARE/poly(U)-binding/degradation factor 1, HDAC5 histone deacetylase 5, HIF-1α hypoxia-inducible factor-1α, LDHA lactate dehydrogenase A, SENP1 SUMO-specific protease 1, SUMO small ubiquitin-like modifier, Tet1 Ten-eleven translocation 1, Ub ubiquitin, USP28 ubiquitin-specific protease 28

Fig. 4

The underlying mechanisms of USP28 in promoting cancer progression. USP28 can promote the development of cancer through deubiquitinating lots of substrates related to tumor progression. A USP28 can promote the progression of cell cycle, aerobic glycolysis and then contribute to the enhancement of cell proliferation. B USP28 accelerates angiogenesis through the mediation of HIF-1α and c-Myc. C Promotion of EMT and metastasis can be induced by USP28. D USP28 suppresses cell differentiation through its deubiquitination on NICD1, LSD1 and Lin28A. E USP28 functions on maintaining cancer stem cell-like characteristics. CD44 cluster of differentiation-44, CDK6 Cyclin-dependent kinase 6, Chk1 checkpoint kinase 1, CLDN7 claudin-7, CSC cancer stem cell, EMT epithelial-mesenchymal transition, FBP1 fructose 1,6-bisphosphatase 1, FOX the Forkhead box, HIF-1α hypoxia-inducible factor-1α, HK2 hexokinase 2, LDHA lactate dehydrogenase A, let-7 lethal-7, LSD1 lysine specific demethylase 1, NICD1 NOTCH1 intracellular domain, Oct4 octamer-binding transcription factor 4, PKM2 M2 isoform of pyruvate kinase, SOX SRY-related HMG box-containing, STAT3 signal transducer and activator of transcription 3, USP28 ubiquitin-specific protease 28

Fig. 5

The underlying mechanisms of USP28 in suppressing cancer progression. USP28 can suppress the development of cancer through deubiquitinating several substrates related to tumor inhibition. A USP28 deubiquitinates tumor suppressors such as p53 and leads to the cell cycle arrest which can induce inhibition of cancers. B USP28 weakens EMT and leads to the suppression of cancer metastasis. BRAF v-raf murine sarcoma viral oncogene homolog B, EMT epithelial-mesenchymal transition, FBW7 F-box and WD repeat domain-containing protein 7, FN-1 fibronectin 1, MAPK mitogen-activated protein kinase, Plk3 polo-like kinase 3, α-SMA α-smooth muscle actin, ub-K119-H2A ubiquitination at K119 of histone H2A, USP28 ubiquitin-specific protease 28