Neuroblastoma (NB) is a malignant tumor originating from neural crest cells and predominantly affects children under 5 years old (1, 2). Accounting for 6%–10% of childhood cancers, NB ranks as the most common extracranial solid tumor in children (3). The heterogeneous pathology and clinical presentations of NB complicate treatment and make prognosis assessment challenging. Current therapeutic approaches encompass surgery, chemotherapy, radiotherapy, and hematopoietic stem cell transplantation. Whereas low-risk patients exhibit a more favorable prognosis, high-risk patients face a notably low 5-year survival rate (4). Although the ganglioside (GD2) monoclonal antibody shows promise in improving NB prognosis, its clinical utility is hindered by severe neuropathic pain and antigen remodeling mechanisms (5). Children's Oncology Group (COG) organized a study called ABNL1221 to explore the effectiveness of the I/T/DIN chemotherapeutic immune-regimen of GD2 monoclonal antibodies combined with irinotecan and temozolomide in the treatment of high-risk recurrent NB. The results of the two studies indicate that the objective response rate of immunochemotherapy in the treatment of highly refractory recurrent NB is only 41.5%–53% (6, 7). Another study from the Barcelona Pediatric Cancer Center explored the efficacy and safety of GD2 monoclonal combined with irinotecan and temozolomide in another regimen called Hu3F8 (H), irinotecan (I), temozolomide (T), and sargramostim (S) (HITS) for the treatment of high-risk recurrent NB. Although the CR rate reached 47% in the group with the best response, the rate of adverse reactions of grade 3 toxicity or greater was 85% (8). An additional series of studies have attempted to further activate the Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) effect of NK cells with the addition of Interleukin-2 (IL-2) and IL-15 cytokines while using GD2 monoclonal antibodies, but differences have been reported between the results. The successful use of GD2 mab in high-risk recurrent NB has improved response rates and prognosis, but only about 50% of the population has benefited. In a pioneering study, third-generation GD2-directed Chimeric Antigen Receptor T-Cell (CAR-T) cell therapy has been administered to individuals with metastatic melanoma and solid tumors like colorectal cancer for the first time, demonstrating its viability, safety, and immune response, but with modest clinical benefits (ACTRN12613000198729). Consequently, researchers are exploring novel treatment strategies to enhance outcomes for high-risk patients with NB (9).

Ubiquitination modification, a crucial post-translational protein modification process, involves the covalent attachment of ubiquitin molecules to target proteins to regulate their stability, activity, and intracellular localization (10). Ubiquitination begins when an enzyme called ubiquitin-activating enzyme (E1) turns on ubiquitin molecules. These molecules are then passed to another enzyme known as ubiquitin-conjugating enzyme (E2). After that, the E2 enzyme links up with a specific enzyme called ubiquitin ligase (E3), which can identify a unique protein that it is looking for. The E3 enzyme helps attach the ubiquitin to a specific spot on this protein, which is a lysine amino acid (10). This process can be iterated to form ubiquitin chains that label substrate proteins for proteasome-mediated degradation or other ubiquitination-dependent regulatory mechanisms (10). Ubiquitination modification has garnered significant attention in the realm of tumor biology, with studies demonstrating its impact on the stability and activity of various tumor suppressors and oncogenes (11, 12).

P53 stands as a preeminent tumor suppressor, central to the mouse double minute 2 homolog (MDM2)/mouse double minute X homolog (MDMX)–p53–negative feedback loop, which includes MDM2 and MDMX proteins (13). This regulatory circuitry is instrumental in modulating essential biological processes, including cancer cell proliferation, growth, cell cycle regulation, apoptosis, senescence, angiogenesis, and immune responses (14). The stability of P53, MDM2, and MDMX is subject to precise control by the ubiquitin-proteasome system (15). In particular, inhibitors of the ubiquitin-specific protease 7 (USP7) have been shown to enhance the degradation of MDM2 and MDMX, liberating and activating p53 to exert its tumor-suppressive functions (15). Ubiquitination also plays a role in governing a plethora of key signaling cascades, such as the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), Nuclear Factor E2-related factor 2 (NRF2), and Hypoxia-inducible factors (HIF) pathways (16–18). Disruptions in ubiquitination can lead to excessive activation of these pathways, fostering the proliferation, differentiation, metabolic activities, and survival of tumor cells (15). Specific E3 ubiquitin ligases contribute to cell cycle dysregulation and unchecked tumor proliferation by promoting the degradation of cell cycle inhibitors (19). In light of ubiquitination’s pivotal function in cancer development and progression, a host of E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) have been identified as promising targets for anti-cancer therapy (12). Research is focused not only on direct inhibitors of enzymes related to ubiquitination but also on enhancing the efficacy of current treatments through the manipulation of ubiquitination processes. For example, bortezomib, a proteasome inhibitor, has been extensively utilized in the management of multiple myeloma (MM) with considerable success (20). The efficacy of proteasome inhibitors in MM treatment underscores the potential of targeting the proteasomal degradation, the final stage of ubiquitination, as a viable therapeutic strategy (20). A phase I study of bortezomib in combination with irinotecan in patients with relapsed/refractory high-risk NB has shown initial effectiveness (21).

Deubiquitination is the opposite of ubiquitination. In this process, enzymes known as DUBs remove ubiquitin labels from proteins. This action stops the proteins from being broken down by a cell’s waste disposal system called the proteasome (22). Targeted inhibition or removal of ubiquitination enzymes can specifically break down proteins of interest. This approach might offer a way to affect proteins that are hard to target with drugs, like some transcription factors (for example, MYCN), enzymes that cause resistance to treatments, and proteins engaged in complicated interactions between different proteins, which usually cannot be addressed by small-molecule drugs (22, 23). Of course, there are two strategies including hydrophobic tagging (HyT) and proteolysis-targeting chimera (PROTAC) have been developed for degrading a broader range of proteins (24, 25). The mostly used hydrophobic moieties include adamantine and BOC3-Arg. HyT had limited applications, because BOC3-Arg was found to inhibit the mammalian target of rapamycin complex 1 (mTORC1) pathway (26). A PROTAC molecule consists of a ligand (mostly small-molecule inhibitor) of the protein of interest (POI) and a ligand of an E3 ubiquitin ligase, upon binding to POI, the PROTAC can recruit E3 for proximity-induced ubiquitination of POI, which is then subjected to degradation by endogenous 26S proteasome (26).

This approach is particularly promising for the treatment of cancers. Delving into the precise mechanisms by which ubiquitination operates in NB is set to enhance our understanding of the tumor’s biology and may unveil new therapeutic targets. This review will thoroughly explore the role of ubiquitination in the etiology, progression, and therapeutic strategies for NB, assessing its viability as a therapeutic target. It is our aspiration that these scholarly endeavors will pave the way for more efficacious and tailored treatment regimens for patients with NB, consequently ameliorating their clinical outcomes and overall quality of life.

In the realm of NB research, a spectrum of high-frequency, high-risk genetic alterations have been pinpointed, encompassing N-MYC amplification, ALK (anaplastic lymphoma kinase) dysregulation, ATRX (alpha thalassemia/mental retardation X-linked) abnormalities, and tumor protein 53 (TP53) mutations (4, 23, 27). Notably, N-MYC amplification stands out as a critical oncogenic event, tightly linked to the exacerbation of disease severity. The MYCN oncogene product, a pivotal transcription factor, sees its stability and functional activity rigorously modulated by the ubiquitination-proteasome axis (28). MYCN’s role in fueling cell cycle advancement and neuronal differentiation is particularly pronounced during embryonic development, positioning it as a compelling target for therapeutic intervention.

A cadre of E3 ubiquitin ligases—encompassing F-box and WD repeat domain containing 7 (Fbxw7), Herpesvirus-associated ubiquitin-specific protease (HAUSP), Tripartite Motif Containing 32 (Trim32), and HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1 (Huwe1)—and deubiquitinases, including USP3 and USP7, orchestrate the fine-tuned ubiquitination-deubiquitination balance of MYCN, thereby dictating its subcellular concentrations and stability (28–30). HAUSP (USP7), a deubiquitinase, is implicated in the deubiquitination of MYCN protein, thereby thwarting its proteasomal degradation (30, 31). Empirical evidence from NB cell lines LAN-1 and SK-N-BE, both characterized by MYCN amplification, supports the notion that HAUSP ablation augments MYCN protein turnover (31). An upregulated HAUSP signature correlates with an ominous prognosis in patients with NB (31). In addition, the expression of Cyclin B1 Interacting Protein 1 (CCNB1IP1) is observed to surge in NB cells with MYCN amplification (29). CCNB1IP1 engages in a competitive binding tussle with Fbxw7 for MYCN, averting its ubiquitination and subsequent proteasome-mediated degradation, culminating in the heightened stability of MYCN protein and the propagation of NB cell proliferation and tumorigenic processes (29).

The tumor suppressor p53, a sentinel regulator of the cell cycle, similarly falls under the regulatory purview of the ubiquitination machinery. The interaction between HAUSP and the p53–Mdm2 complex, leading to p53’s deubiquitination, stands as a seminal example of the role DUBs play in protein stability regulation (32). Ubiquitinated p53 is conventionally targeted for degradation by the 26S proteasome, a pivotal mechanism for intracellular p53 homeostasis (32). The P300 protein, in its capacity as a transcriptional coactivator, also wields ubiquitin ligase capabilities, further influencing p53 ubiquitination (33). The stabilization of p53 through deubiquitination, mitigating its proteasomal degradation, is instrumental in its antitumor function in NB (34). Moreover, an innovative strategy leveraging the ubiquitination-proteasome system involves harnessing USP7 inhibitors to enhance the ubiquitination of the MDM2/MDMX negative regulatory elements within the p53 regulatory loop, thereby amplifying p53’s anti-NB efficacy (30). The focus is on highlighting that this mechanism is relevant for individuals capable of producing a functional p53 protein, and it may not be applicable to patients with NB with TP53 gene mutations (30, 32). Nonetheless, investigations into the role of ubiquitination in other high-risk mutations associated with NB, beyond MYCN, remain sparse, potentially attributable to the infrequent occurrence of these alterations.

UBE4B, an E3/E4 ubiquitin ligase, has been found to be negatively correlated with epidermal growth factor receptor (EGFR) levels in NB, with the degradation rate of EGFR being closely associated with the levels of UBE4B within cells (35–37). Enhanced catalytic activity of UBE4B leads to reduced sensitivity to EGFR inhibitors (37). Depletion of UBE4B significantly inhibits NB proliferation and migration and augments the apoptotic response to the EGFR inhibitor Cetuximab (37). UBE4B can also form a complex with ITCH, promoting the Lys48/Lys63 branched ubiquitination and proteasomal degradation of Ku70 and c-FLIPL, resulting in increased apoptosis of NB cells (36). The TRIM (tripartite motif) protein family, through its E3 ubiquitin ligase activity, is involved in the regulation of various biological processes in NB, including tumor suppression and oncogenic processes (38). For instance, TRIM11 regulates neurogenesis by ubiquitinating PAX6, whereas TRIM16 promotes cell differentiation by enhancing the transcriptional activity of RARβ (38). TRIM21 facilitates cancer proliferation by ubiquitinating various cancer-promoting proteins (such as NF-κB, STAT3, BCL2, p53, p27, and Snail) and promotes their proteasomal degradation by increasing their ubiquitination (39, 40). Similarly, the E3 ligase Makorin Ring Finger Protein 2 (MKRN2) has been shown to regulate the proliferation and migration of human NB SHSY5Y cells by ubiquitinating Insulin-like Growth Factor 2 mRNA-binding Protein 3 (IGF2BP3) (41). These findings underscore the significance of UBE4B, the TRIM protein family, and MKRN2 in NB cell proliferation, apoptosis, and migration.

One of the hallmarks of NB is the impairment of cellular differentiation, which is critical for tumor formation. REST (repressor element-1 silencing transcription factor) is a key transcriptional repressor essential for the maintenance, self-renewal, and differentiation of NB (42). The deubiquitinase USP3 interacts with REST, stabilizing and prolonging the half-life of REST protein, thereby counteracting its ubiquitination in NB (42, 43). Silencing of USP3 reduces the self-renewal capacity of NB cells and promotes differentiation induced by retinoic acid. The absence of USP3 in vitro and in vivo models has been shown to decrease NB cell proliferation, migration, and invasion and inhibit tumor growth (43). The SCFβ– β-transducin repeat-containing protein (TRCP) (Skp1/Cullin/F-box protein β–TRCP) complex also regulates neuroblast differentiation by degrading REST protein, which is one of the mechanisms by which retinoic acid promotes NB differentiation (44). The accumulation and impaired degradation of inhibitory differentiation proteins represent another factor hindering the differentiation of NB cells. Xuan Li et al. discovered that calcium/calmodulin-dependent protein kinase II can promote the autophagy of inhibitory differentiation proteins through the ubiquitination pathway, thereby facilitating NB cell differentiation (45). Cylindromatosis (CYLD), another deubiquitinase, is associated with tumorigenesis due to the loss of its activity and regulates the NF-κB signaling pathway by removing Lys63 and linear-linked ubiquitin chains from substrates (46). Retinoic acid–mediated NB differentiation restores CYLD expression and promotes CYLD SUMOylation (46). This post-translational modification inhibits CYLD’s deubiquitination activity toward TRAF2 and TRAF6, activating the NF-κB signaling pathway. Overexpression of non-SUMOylated CYLD mutants in NB cells reduces retinoic acid–induced NF-κB activation and cell differentiation (46).

Inhibiting the ubiquitin-proteasome system to manipulate the degradation of targeted substrate proteins represents a pivotal approach in therapeutic discovery. Human cells harbor a diverse array of over 100 deubiquitinases, categorized into seven distinct families based on structural attributes, including ubiquitin-specific proteases (USPs), ubiquitin C-terminal hydrolases (UCHs), and ovarian tumor (OTU) proteases (47). The USP family stands out for its comprehensive characterization in structural and functional studies, as well as for the abundance of literature on its small-molecule modulators.

USP5, a deubiquitinase enzyme, plays a role in regulating the binding between E3 ubiquitin ligases and their substrate proteins. SE486-11 has been crafted as an inhibitor of USP5 for NB therapeutics (48). This compound exhibits potent activity against NB cells (IC50 ≤ 2 µM) and demonstrates minimal cytotoxicity to normal cells (IC50 ≥ 15 µM). The mechanism by which SE486-11 operates involves modulating USP5 to enhance MYCN ubiquitination while also potentiating the effects of histone deacetylase (HDAC) inhibitors (48). Formononetin, a natural USP5 inhibitor identified in plants such as Trifolium pratense, is known for its array of physiological effects, including anti-neurodegenerative properties (49). It prompts cell death in the neuronal cell line SH-SY5Y by engaging the PI3K/Akt-Nrf2 antioxidant gene pathway and inhibiting MAPK-mediated apoptosis (49). Suramin, another recognized USP5 inhibitor, exerts cytostatic effects at concentrations ranging from 50 to 400 µg/mL in SH-SY5Y cells (50). Flow cytometric analysis of cells treated with Suramin indicates a halt in the G1/G0 phase of the cell cycle (50). Nevertheless, a conflicting study has shown that Suramin at 100 µM concentration effectively shields cerebellar neurons and NB-2a cells from apoptosis, as evidenced by the suppression of caspase 3–like activity in NB-2a cells and the prevention of both high molecular weight (HMW) and internucleosomal DNA fragmentation (51). This discrepancy raises the intriguing possibility that varying concentrations and doses of USP inhibitors could exert differential biological responses in identical tumor cell lines.

USP7 (also known as HAUSP) was identified as a regulator of MYCN function in NB (31). HAUSP interacts with MYCN protein, inducing its deubiquitination and subsequent stabilization (31). Conversely, RNA interference–mediated knockdown of USP7 in NB cancer cell lines or genetic ablation of USP7 in mouse models disrupts MYCN stability, thereby inhibiting its function. Notably, HAUSP is more abundant in patients with NB with poorer prognosis, and its expression is significantly correlated with MYCN transcriptional activity. Additionally, small-molecule inhibitors of USP7 have been shown to significantly inhibit the growth of human NB cells with MYCN amplification in xenograft mouse models (31).

P22077, a representative small-molecule inhibitor of USP7, has been validated for its ability to induce MYCN protein degradation and inhibit NB cell growth (31). Its effects are particularly pronounced in cell lines with MYCN amplification and in xenograft models (31). Interestingly, P22077 can strongly induce apoptosis in NB cells with an intact USP7–HDM2–p53 axis but not in cells with p53 mutation or lacking human MDM2 homolog (HDM2) expression (52). P22077 stabilizes p53 by promoting HDM2 protein degradation and significantly enhances the cytotoxicity of doxorubicin (Dox) and etoposide (VP-16) to NB cells (52). Furthermore, P22077 can also re-sensitize chemo-resistant NB cells (LA-N-6) to chemotherapy. Another study showed that BIRC5/Survivin inhibitor, YM155, specifically inhibits the growth of MYCN-amplified (MNA) NB cells in vitro and inhibits USP7 deubiquitinase activity in vitro using Ub-amino methyl coumarin (Ub-AMC) as a substrate (53). In vivo studies further demonstrated that YM155 significantly inhibited tumor growth in the MNA NB xenograft model (53). These findings suggest that USP7 inhibitors may represent a novel approach for treating high-risk NB with MYCN amplification and non-p53 mutations, both as a monotherapy and as an effective adjunct to existing chemotherapy regimens.

b-AP15, a small-molecule inhibitor targeting USP14, has been shown to induce apoptosis and inhibit cell proliferation in NB. In SH-SY5Y xenograft mouse models, b-AP15 also significantly inhibited tumor growth. When used in combination with traditional chemotherapy drugs such as doxorubicin or VP-16, b-AP15 exerts synergistic antitumor effects on NB (54). Preclinical studies are ongoing regarding the use of the USP family as a monotherapy or in combination with existing chemotherapy regimens for NB treatment. Other similar targets include USP22 (55), USP3 (56), USP29 (57), as well as small ubiquitin-like modifiers (SUMOs) or SUMOylation.

NVP-BEZ235 is a dual kinase inhibitor targeting both PI3K and mTOR kinases and has been shown to inhibit NB cell proliferation and induce cell cycle arrest at the G0/G1 phase (58, 59). One of its mechanisms may involve activating GSK3β (glycogen synthase kinase 3β) to trigger the ubiquitin-proteasome pathway degradation of cyclin D1 and E1. NVP-BEZ235 has also shown similar anti-proliferative effects in NB xenograft mouse models (59). Some researchers have found that targeting the PI3K/Akt/mTOR signaling pathway can enhance chemotherapy sensitivity in NB (60).

ARV-825 is a novel extra terminal (Bromodomain and Extra Terminal domain (BET)) inhibitor using PROTAC technology that degrades target proteins by the proteasome. Inhibition of bromodomain and BET proteins shows great potential in multiple of Myc-driven tumors. A study showed that ARV-825 treatment robustly induced proliferative suppression, cell cycle arrest, and apoptosis in NB cells. Moreover, ARV-825 efficiently depleted BET protein expression, subsequently repressing the expression of MYCN or c-Myc. In the NB xenograft model, ARV-825 profoundly reduced tumor growth and led to the downregulation of BRD4 and MYCN expression in mice (61).

MZ1 is a novel BET inhibitor that employs PROTAC technology for proteasomal degradation of target proteins and has shown excellent effects in some tumors. A study observed that MZ1 suppressed MYC-amplified NB cell proliferation and normal cell cycle while simultaneously boosting cell apoptosis. MZ1 also provides a significant therapeutic impact in vivo, which imply that MZ1 might be exploited as a possible therapeutic method for NB therapy (62).

In summary, preclinical research on NB primarily focuses on USP5, USP7, USP14, and some key signaling pathway kinase inhibitors. BET inhibitors based on PROTAC technology have been studied in a small number of NB studies, which tentatively demonstrate the possibility of future targeted therapies for MYC-driven tumors. Other USP inhibitors, including PYR-41, WP1130, Tolmidine, vialinin A, gossypetin, and some proteasome inhibitors, have shown promising results in preclinical studies of other cancers but are relatively understudied in NB (63, 64).

The potential of targeting the disrupted UPS in MM was first established with the introduction of the first-in-class proteasome inhibitor bortezomib. The small-molecule inhibitor VLX1570 and its analog b-AP15 specifically inhibit the activity of USP14 and Ubiquitin Carboxyl-Terminal Hydrolase L5 (UCHL5) within the 19S regulatory subunit. In a phase I clinical trial for patients with refractory/relapsed MM, VLX1570 was administered to 14 participants. Notable antitumor effects were observed at doses exceeding 0.6 mg/kg. The trial was halted due to severe lung damage and bone marrow failure in two patients, but the observed antitumor activity corroborated preclinical findings (65). Other agents under investigation include KSQ-4279, an allosteric inhibitor of USP1, and a selective inhibitor of USP30, both of which are being evaluated in phase 1 clinical trials for solid tumors and chronic kidney disease, respectively (66, 67). The first study of bortezomib in children with refractory solid tumors was ADVL0015 to evaluate the safety and efficacy of bortezomib in 15 children with refractory solid tumors. However, no objective response was observed in 11 evaluable patients (68). Another phase I study of bortezomib in combination with irinotecan in patients with relapsed/refractory high-risk NB showed that two of 17 (12%) evaluable patients showed objective responses lasting more than 40 courses, including one partial remission and one complete remission. Four patients (23%) had prolonged stable disease (SD) lasting six or more courses, with a total of 35% study patients demonstrating clinical benefit in the form of prolonged Objective reaction (OR) or SD (21).

1. Min J, Wu Y, Huang S, Li Y, Lv X, Tang R, et al. Serum cholesterol level as a predictive biomarker for prognosis of Neuroblastoma. BMC Pediatr. (2024) 24:205. doi: 10.1186/s12887-024-04700-7

PubMed Abstract | Crossref Full Text | Google Scholar

2. Tan J, Wang C, Jin Y, Xia Y, Gong B, Zhao Q. Optimal combination of MYCN differential gene and cellular senescence gene predicts adverse outcomes in patients with neuroblastoma. Front Immunol. (2023) 14:1309138. doi: 10.3389/fimmu.2023.1309138

PubMed Abstract | Crossref Full Text | Google Scholar

3. Hu X, Zhou Y, Hill C, Chen K, Cheng C, Liu X, et al. Identification of MYCN non-amplified neuroblastoma subgroups points towards molecular signatures for precision prognosis and therapy stratification. Br J Cancer. (2024) 130:1841–54. doi: 10.1038/s41416-024-02666-y

PubMed Abstract | Crossref Full Text | Google Scholar

4. Bellini A, Potschger U, Bernard V, Lapouble E, Baulande S, Ambros PF, et al. Frequency and prognostic impact of ALK amplifications and mutations in the European neuroblastoma study group (SIOPEN) high-risk neuroblastoma trial (HR-NBL1). J Clin Oncol: Off J Am Soc Clin Oncol. (2021) 39:3377–90. doi: 10.1200/JCO.21.00086

Crossref Full Text | Google Scholar

5. Li H, Zhao J, Yang J, Tang J, Zhang T, Jiang H, et al. Bone marrow relapse in stage 4 neuroblastoma of children in Shanghai. Am J Cancer Res. (2024) 14:145–54. doi: 10.62347/ZMWQ3581

PubMed Abstract | Crossref Full Text | Google Scholar

6. Mody R, Naranjo A, Van Ryn C, Yu AL, London WB, Shulkin BL, et al. Irinotecan-temozolomide with temsirolimus or dinutuximab in children with refractory or relapsed neuroblastoma (COG ANBL1221): an open-label, randomised, phase 2 trial. Lancet Oncol. (2017) 18:946–57. doi: 10.1016/S1470-2045(17)30355-8

PubMed Abstract | Crossref Full Text | Google Scholar

7. Mody R, Yu AL, Naranjo A, Zhang FF, London WB, Shulkin BL, et al. Irinotecan, temozolomide, and dinutuximab with GM-CSF in children with refractory or relapsed neuroblastoma: A report from the children's oncology group. J Clin Oncol. (2020) 38:2160–9. doi: 10.1200/JCO.20.00203

PubMed Abstract | Crossref Full Text | Google Scholar

8. Munoz JP, Larrosa C, Chamorro S, Perez-Jaume S, Simao M, Sanchez-Sierra N, et al. Early salvage chemo-immunotherapy with irinotecan, temozolomide and naxitamab plus GM-CSF (HITS) for patients with primary refractory high-risk neuroblastoma provide the best chance for long-term outcomes. Cancers (Basel). (2023) 15:4837. doi: 10.3390/cancers15194837

PubMed Abstract | Crossref Full Text | Google Scholar

10. Liu BQ, Jin J, Li YY. Ubiquitination modification: critical regulation of IRF family stability and activity. Sci China Life Sci. (2021) 64:957–65. doi: 10.1007/s11427-020-1796-0

PubMed Abstract | Crossref Full Text | Google Scholar

11. Wang T, Li X, Ma R, Sun J, Huang S, Sun Z, et al. Advancements in colorectal cancer research: Unveiling the cellular and molecular mechanisms of neddylation (Review). Int J Oncol. (2024) 64:39. doi: 10.3892/ijo.2024.5627

PubMed Abstract | Crossref Full Text | Google Scholar

12. Zhang SL, Zhang SJ, Li L, Zhang YW, Wang Z, Wang L, et al. NAP1L1 regulates BIRC2 ubiquitination modification via E3 ubiquitin ligase UBR4 and hence determines hepatocellular carcinoma progression. Cell Death Discov. (2024) 10:154. doi: 10.1038/s41420-024-01927-2

PubMed Abstract | Crossref Full Text | Google Scholar

15. Qi SM, Cheng G, Cheng XD, Xu Z, Xu B, Zhang WD, et al. Targeting USP7-mediated deubiquitination of MDM2/MDMX-p53 pathway for cancer therapy: are we there yet? Front Cell Dev Biol. (2020) 8:233. doi: 10.3389/fcell.2020.00233

PubMed Abstract | Crossref Full Text | Google Scholar

16. Glaviano A, Foo ASC, Lam HY, Yap KCH, Jacot W, Jones RH, et al. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol Cancer. (2023) 22:138. doi: 10.1186/s12943-023-01827-6

PubMed Abstract | Crossref Full Text | Google Scholar

17. Kim JH, Khalil AAK, Kim HJ, Kim SE, Ahn MJ. 2-Methoxy-7-Acetonyljuglone Isolated from Reynoutria japonica Increases the Activity of Nuclear Factor Erythroid 2-Related Factor-2 through Inhibition of Ubiquitin Degradation in HeLa Cells. Antioxidants. (2019) 8:398. doi: 10.3390/antiox8090398

PubMed Abstract | Crossref Full Text | Google Scholar

18. Lee JH, Elly C, Park Y, Liu YC. E3 ubiquitin ligase VHL regulates hypoxia-inducible factor-1alpha to maintain regulatory T cell stability and suppressive capacity. Immunity. (2015) 42:1062–74. doi: 10.1016/j.immuni.2015.05.016

PubMed Abstract | Crossref Full Text | Google Scholar

19. Zhao M, Hu M, Chen Y, Liu H, Chen Y, Liu B, et al. Cereblon modulator CC-885 induces CRBN-dependent ubiquitination and degradation of CDK4 in multiple myeloma. Biochem Biophys Res Commun. (2021) 549:150–6. doi: 10.1016/j.bbrc.2021.02.110

PubMed Abstract | Crossref Full Text | Google Scholar

20. Richardson PG, Trudel S, Popat R, Mateos MV, Vangsted AJ, Ramasamy K, et al. Mezigdomide plus dexamethasone in relapsed and refractory multiple myeloma. N Engl J Med. (2023) 389:1009–22. doi: 10.1056/NEJMoa2303194

PubMed Abstract | Crossref Full Text | Google Scholar

21. Mody R, Zhao L, Yanik GA, Opipari V. Phase I study of bortezomib in combination with irinotecan in patients with relapsed/refractory high-risk neuroblastoma. Pediatr Blood Cancer. (2017) 64:e26563. doi: 10.1002/pbc.26563

Crossref Full Text | Google Scholar

23. Wolpaw AJ, Bayliss R, Buchel G, Dang CV, Eilers M, Gustafson WC, et al. Drugging the "Undruggable" MYCN oncogenic transcription factor: overcoming previous obstacles to impact childhood cancers. Cancer Res. (2021) 81:1627–32. doi: 10.1158/0008-5472.CAN-20-3108

PubMed Abstract | Crossref Full Text | Google Scholar

24. Neklesa TK, Tae HS, Schneekloth AR, Stulberg MJ, Corson TW, Sundberg TB, et al. Small-molecule hydrophobic tagging-induced degradation of HaloTag fusion proteins. Nat Chem Biol. (2011) 7:538–43. doi: 10.1038/nchembio.597

PubMed Abstract | Crossref Full Text | Google Scholar

25. Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc Natl Acad Sci U S A. (2001) 98:8554–9. doi: 10.1073/pnas.141230798

PubMed Abstract | Crossref Full Text | Google Scholar

26. Coffey RT, Shi Y, Long MJ, Marr MT 2nd, Hedstrom L. Ubiquilin-mediated small molecule inhibition of mammalian target of rapamycin complex 1 (mTORC1) signaling. J Biol Chem. (2016) 291:5221–33. doi: 10.1074/jbc.M115.691584

PubMed Abstract | Crossref Full Text | Google Scholar

27. Qadeer ZA, Valle-Garcia D, Hasson D, Sun Z, Cook A, Nguyen C, et al. ATRX in-frame fusion neuroblastoma is sensitive to EZH2 inhibition via modulation of neuronal gene signatures. Cancer Cell. (2019) 36:512–527 e519. doi: 10.1016/j.ccell.2019.09.002

PubMed Abstract | Crossref Full Text | Google Scholar

28. Cheung BB, Kleynhans A, Mittra R, Kim PY, Holien JK, Nagy Z, et al. A novel combination therapy targeting ubiquitin-specific protease 5 in MYCN-driven neuroblastoma. Oncogene. (2021) 40:2367–81. doi: 10.1038/s41388-021-01712-w

PubMed Abstract | Crossref Full Text | Google Scholar

29. Zhou Y, Yan H, Zhou Q, Wang P, Yang F, Yuan Z, et al. CCNB1IP1 prevents ubiquitination-mediated destabilization of MYCN and potentiates tumourigenesis of MYCN-amplificated neuroblastoma. Clin Trans Med. (2023) 13:e1328. doi: 10.1002/ctm2.1328

Crossref Full Text | Google Scholar

30. Le Clorennec C, Lee K, Huo Y, Zage PE. USP7 Inhibition Suppresses Neuroblastoma Growth via Induction of p53-Mediated Apoptosis and EZH2 and N-Myc Downregulation. Int J Mol Sci. (2023) 24:13780. doi: 10.3390/ijms241813780

PubMed Abstract | Crossref Full Text | Google Scholar

33. Grossman SR, Deato ME, Brignone C, Chan HM, Kung AL, Tagami H, et al. Polyubiquitination of p53 by a ubiquitin ligase activity of p300. Science. (2003) 300:342–4. doi: 10.1126/science.1080386

PubMed Abstract | Crossref Full Text | Google Scholar

34. Cheng C, He T, Chen K, Cai Y, Gu Y, Pan L, et al. P300 interacted with N-myc and regulated its protein stability via altering its post-translational modifications in neuroblastoma. Mol Cell Proteom: MCP. (2023) 22:100504. doi: 10.1016/j.mcpro.2023.100504

Crossref Full Text | Google Scholar

35. Antoniou N, Lagopati N, Balourdas DI, Nikolaou M, Papalampros A, Vasileiou PVS, et al. The role of E3, E4 ubiquitin ligase (UBE4B) in human pathologies. Cancers. (2019) 12:62. doi: 10.3390/cancers12010062

PubMed Abstract | Crossref Full Text | Google Scholar

36. Le Clorennec C, Subramonian D, Huo Y, Zage PE. UBE4B interacts with the ITCH E3 ubiquitin ligase to induce Ku70 and c-FLIPL polyubiquitination and enhanced neuroblastoma apoptosis. Cell Death Dis. (2023) 14:739. doi: 10.1038/s41419-023-06252-7

PubMed Abstract | Crossref Full Text | Google Scholar

37. Zage PE, Sirisaengtaksin N, Liu Y, Gireud M, Brown BS, Palla S, et al. UBE4B levels are correlated with clinical outcomes in neuroblastoma patients and with altered neuroblastoma cell proliferation and sensitivity to epidermal growth factor receptor inhibitors. Cancer. (2013) 119:915–23. doi: 10.1002/cncr.27785

PubMed Abstract | Crossref Full Text | Google Scholar

40. Wang F, Wu Z, Li Q, Ni Z, Wang C, Lu J. Ubiquitination of p21 by E3 ligase TRIM21 promotes the proliferation of human neuroblastoma cells. Neuromol Med. (2021) 23:549–60. doi: 10.1007/s12017-021-08661-3

Crossref Full Text | Google Scholar

41. Jia C, Tang H, Yang Y, Yuan S, Han T, Fang M, et al. Ubiquitination of IGF2BP3 by E3 ligase MKRN2 regulates the proliferation and migration of human neuroblastoma SHSY5Y cells. Biochem Biophys Res Commun. (2020) 529:43–50. doi: 10.1016/j.bbrc.2020.05.112

PubMed Abstract | Crossref Full Text | Google Scholar

42. Singh A, Rokes C, Gireud M, Fletcher S, Baumgartner J, Fuller G, et al. Retinoic acid induces REST degradation and neuronal differentiation by modulating the expression of SCF(beta-TRCP) in neuroblastoma cells. Cancer. (2011) 117:5189–202. doi: 10.1002/cncr.26145

PubMed Abstract | Crossref Full Text |