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Azhar, A. UPS in Human Malignancies. Encyclopedia. Available online: https://encyclopedia.pub/entry/8526 (accessed on 04 July 2024).
Azhar A. UPS in Human Malignancies. Encyclopedia. Available at: https://encyclopedia.pub/entry/8526. Accessed July 04, 2024.
Azhar, Ali. "UPS in Human Malignancies" Encyclopedia, https://encyclopedia.pub/entry/8526 (accessed July 04, 2024).
Azhar, A. (2021, April 08). UPS in Human Malignancies. In Encyclopedia. https://encyclopedia.pub/entry/8526
Azhar, Ali. "UPS in Human Malignancies." Encyclopedia. Web. 08 April, 2021.
UPS in Human Malignancies
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This entry is adapted from the peer-reviewed paper 10.3390/cancers13071513

The ubiquitin proteasome system (UPS) governs the non-lysosomal degradation of oxidized, damaged, or misfolded proteins in eukaryotic cells. This process is tightly regulated through the activation and transfer of polyubiquitin chains to target proteins which are then recognized and degraded by the 26S proteasome complex. The role of UPS is crucial in regulating protein levels through degradation to maintain fundamental cellular processes such as growth, division, signal transduction, and stress response. Dysregulation of the UPS, resulting in loss of ability to maintain protein quality through proteolysis, is closely related to the development of various malignancies and tumorigenesis.

ubiquitin proteasome system dysregulation chemoresistance cancer therapy inhibitors

1. The Ubiquitin Proteasome System

The ubiquitin proteasome system (UPS) is essential for the regulation of protein homeostasis and control of eukaryotic cellular processes including cell cycle progression, stress response, signal transduction, and transcriptional activation [1][2]. UPS controls the degradation of approximately 80% of intracellular proteins which are oxidized, damaged, or misfolded in eukaryotic cells [3]. Though the UPS and autophagy are both important systems of degradation of proteins, the sizes of substrates critically influence the choice of degradation pathway [4]. The UPS typically degrades single unfolded polypeptides, whereas autophagy deals with larger cytosolic complexes, cellular aggregates, and organelles.

Degradation of targeted proteins involves a tightly coordinated process where ubiquitin is covalently attached to the substrate protein through the sequential action of three enzymes. Ubiquitin is a small protein comprising 76 amino acids found in all eukaryotic cells [5]. The energy derived from ATP hydrolysis initiates the activation of ubiquitin activating enzyme (E1) allowing the formation of thioester bond between E1 and ubiquitin. This is followed by transfer of ubiquitin from E1 to ubiquitin-conjugating enzyme (E2), forming a thioester bond similar to that of E1. The third final step involves the covalent attachment of ubiquitin to lysine residues of target protein, catalyzed by ubiquitin ligase (E3) [6]. The 26S proteasome complex comprises a core 20S proteasome and one or two units of the regulatory 19S proteasome (Figure 1). Once a target protein has been modified with a polyubiquitin chain, it is recognized by the 19S proteosome which removes the polyubiquitin chain and the protein is then unfolded and translocated into the 20S proteasome where it is degraded into short peptides [7]. While polyubiquitination has been associated with protein clearance through proteasomal degradation, mono-ubiquitination, which involves the addition of a single ubiquitin moiety to the substrate protein, is shown to affect a range of cellular processes including kinase activity, epigenetic regulation, protein translocation, and DNA damage signaling [8][9].

Cancers 13 01513 g001 550

Figure 1. Overview of the ubiquitin proteasome system (UPS). The UPS cascade. Substrate protein is ubiquitinated through the sequential action of three enzymes. E1 binds to activated ubiquitin and is transferred to the ubiquitin-conjugating enzyme (E2). The E2 carries the activated ubiquitin to ubiquitin ligase (E3), which then facilitates the transfer of ubiquitin from E2 to a lysine residue in the target protein. Proteins can be modified with a single mono-ubiquitin molecule, or with ubiquitin chains of different lengths and linkage types. Substrate proteins modified with specific chains are recognized and subsequently degraded by the 26S proteasome. Deubiquitinating enzymes (DUBs) remove ubiquitin from substrate proteins by removing mono-ubiquitination or by trimming or removing the ubiquitin chain. Typically, poly-ubiquitination has been associated with protein clearance through proteasomal degradation while mono-ubiquitination which involves the addition of a single ubiquitin moiety to the substrate protein affects cellular processes.

 

Ubiquitin contains seven important lysine residues which can be ubiquitinated (K6, K11, K27, K33, K48, and K63) and can form polyubiquitin chains. The two best characterized ubiquitin linkages are K48 and K63 where K48 polyubiquitination targets proteins for degradation by the 26S proteasome complex [10] and K63 participates in DNA damage signaling and recruits DNA repair proteins to damage sites [11]. Protein ubiquitination can be reversed through the removal of ubiquitin from target proteins by deubiquitinating enzymes (DUBs), and this rescues protein destined for degradation. DUBs have also been implicated in the maturation, recycling, and editing of ubiquitin [12][13][14]. Further, chain configuration and linkage can endow ubiquitin with additional roles through the formation of more complex topologies with unknown activities [15]. Dysregulation or abnormal UPS function is frequently seen in various human malignancies and this identifies the aberrant components of the UPS as potential drug targets [16][17]. This review endeavors to present recent literature on the functional roles of UPS in human cancers. We cover how the dysregulation of UPS components may function either as an oncogene or tumor suppressor and affects cellular signaling in tumors. Further, we present current small inhibitors against the UPS and highlight issues that has severely restricted its development.

Increasing evidence demonstrate ubiquitin enzymes are important in carcinogenesis. Though there are numerous cancer-related studies on these enzymes, a large majority primarily focuses on E3 ligases. Studies on E1-activating enzymes have been largely used to identify potential targets in UPS inhibition in cancer while studies on E2-conjugated enzymes revealed their involvement in cell cycle progression, DNA repair, and regulation of oncogenic signaling pathways during tumorigenesis [18][19]. Further E2 enzymes are often found upregulated and highly correlated with poor prognosis in various malignancies including the pancreas, lung, breast, skin, and thyroid [20]. Currently, eight E1s, > 40 E2s, and > 600 E3s have been identified in the human proteome [21].

 

2. Dysregulation of UPS in cancer

2.1. E2 enzymes

The ubiquitin-conjugating E2 family comprises > 40 members, and modulates protein stability and ubiquitination through the conjugation of ubiquitin to target proteins [22]. E2-conjugating enzymes are also found dysregulated in cancers and reported to be potent mediators contributing towards multiple tumorigenic processes including migration/invasion, proliferation, drug resistance, radiation resistance, cell cycle, apoptosis, and stimulation of oncogenic pathways. Examples of dysregulated E2 enzymes in cancer are summarized in Table 1  

Table 1. Summary of the functions of E2 and E3 enzymes in human cancers described in this review.

Family Name Role Cancer Type Function Test Model Reference
E2 UBE2C Oncogene Gastric Chromosomal stability, Proliferation, Migration, Invasion In vitro, In vivo [23]
    Oncogene Colon Cell cycle, Proloferation In vitro [24]
    Oncogene Colorectal Proliferation, Invasion In vitro [25]
    Oncogene Thyroid Proliferation In vitro [26]
    Oncogene Breast Proliferation, Drug resistance, Radiation resistance In vitro [27]
    Oncogene Liver Proliferation, Drug resistance, Migration, Invasion In vitro [28]
    Oncogene Non-small cell lung Drug resistance In vitro [29]
  UBE2Q1 Oncogene Colorectal Proliferation   [30]
    Oncogene Liver p53 signaling, Cell cycle In vitro [31]
    Oncogene Breast p53 signaling In vitro [32]
  UBE2S Oncogene Endometrial SOX6/β-catenin signaling, Proliferation In vitro [33]
    Oncogene Lung adenocarcinoma Proliferation, p53 signaling, Apoptosis In vitro [34]
    Oncogene Liver p53 signaling, Cell cycle In vitro [35]
E3 FBW7 Tumor suppressor Burkitt’s lymphoma c-Myc signaling In vitro [36][37]
    Tumor suppressor Chronic myelogenous leukemia c-Myc signaling In vitro, In vivo [38]
    Lipogenesis Lung, Melanoma, Thyroid, Cervical mTORC2/SREBP1 signaling In vitro [39]
    Tumor suppressor T cell leukemia Notch signaling In vitro, In vivo [40]
    Tumor suppressor Colorectal c-Myc signaling, Cell cycle In vitro [41]
    Tumor suppressor Esophageal squamous cell c-Myc signaling In vitro [42]
    Tumor suppressor Colorectal, Cervical, Ovarian, Non-small cell lung Apoptosis (via Mcl1) In vitro [43]
  MDM2 Oncogene Neuroblastoma p53 signaling In vitro, In vivo [44]
    Oncogene Cervical Cell cycle, Apoptosis In vitro [45]
    Oncogene Liver Metastasis, Drug response In vitro, In vivo [46]
  Cdc20 Oncogene Breast Metastasis, Drug response In vitro [47]
  Cdh1 Tumor suppressor Breast Src signaling In vitro [48]
  β-TRCP Tumor suppressor Breast, Prostate MTSS1 signaling In vitro [49]
    Oncogene Lung FOXN2 In vitro, In vivo [50]
    Tumor suppressor Papillary thyroid VEGFR2 signaling In vitro, In vivo [51]
  E6AP Oncogene Prostate Radiation response In vitro [52]
    Oncogene Prostate p27 signaling In vitro, In vivo [53]
    Oncogene Prostate Metastasis In vitro, In vivo [54]
2.2. E3 Ligases

E3 ubiquitin ligases are a large family of enzymes that promote ubiquitin transfer to proteins or polyubiquitin chains [55]. E3 ligases play an important role in the ubiquitin- mediated proteolytic cascade and are classified into four main classes, according to their domain structure and substrate recognition. The four E3 classes are the homologous to the E3 ubiquitin ligase E6-associated protein (E6AP) C-terminus (HECT), really interesting new gene (RING)-finger, U-box, and plant homeodomain (PHD)-finger. Depending on the substrate targets, E3 ligases can function either as a tumor suppressor or oncogene and can participate in various cellular processes including cell cycle, apoptosis, drug response, metastasis, radiation response, and oncogenic signaling. Examples of dysregulation of E3 ligases in cancer are summarised in Table 1. 

2.3. Deubiquitinating enzymes (DUBs)

Currently, about >100 DUB genes have been identified where the biological functions for the majority are still unknown [56][57]. USPs are, by far, the largest class of DUBs, com- prising ~60 human proteases with most containing several domains apart from the catalytic domain. Conserved sequences among these proteases are restricted to the catalytic domain which is designated by the catalytic motif containing Cys, His, and Asp (or Asn) residues. Conserved catalytic domains are thought to be important for substrate specificity, catalytic activity regulation, and mediating protein–protein interaction to each USP. Dysregulated DUBs in cancer are hence potential drug targets. The challenge in the development of drugs is the difficulty in designing a specific inhibitor for a single DUB. 3D crystallography structures of catalytic domains of USP2, USP7, USP8, and USP14 reveal a remarkable structural conservation of their active site shared among these enzymes, thus providing evidence that the development of inhibitors may prove to be challenging [58][59][60]. Further, the crystal structures show that the catalytic domains are in inactive conformation prior ubiquitin binding suggesting an alternative target for intervention. Apart from deubiquitination, DUBs have been shown to modulate cellular processes in human malignancies including DNA damage response, oncogenic signaling cascades, drug resistance, apoptosis, cell cycle, immunomodulation, and invasion/migration. Examples of dysregulated DUBs in cancer are summarised in Table 2. 

Table 2. Summary of the functions of DUB enzymes described in this review.

Name Role Cancer Type Function Test model Reference
BAP1 Tumor suppressor Lung, Osteosarcoma, Colon DNA double-strand repair In vitro [61][62][63]
  Tumor suppressor Renal Ferroptosis signaling In vitro [64]
USP7 Oncogene Lung p53 signaling In vitro, in vivo [65]
  Oncogene Cervical Self-renewal; Foxp3 signaling In vitro [66]
  Oncogene Non-small cell lung Immune Response; Foxp3 signaling In vitro [67]
USP22 Oncogene Lung Cell Cycle In vitro [68]
  Oncogene Lung adenocarcinoma EGFR-TKI resistance In vitro, in vivo [69]
  Oncogene Colon CCNB1 signaling In vitro, in vivo [70]
  Oncogene Glioblastoma KDM1A signaling In vitro, in vivo [71]
UCHL1 Oncogene Breast Drug resistance; Invasion/migration In vitro [72]
Ataxin 3 Oncogene Breast, Osteosarcoma, Cervical, Colorectal DNA  In vitro [73]
  Oncogene Testicular mTOR/Akt signaling In vitro [74]
PSMD11 Oncogene Cervical. Osteosarcoma DNA damage response In vitro [75]
  Oncogene Lung, Prostate, Colorectal, Breast, Cervix Cell cycle In vitro [76]
  Oncogene Liver E2F1 signaling In vitro, in vivo [77]
A20 Tumor suppressor Colorectal Apoptosis signaling In vitro [78]
  Tumor suppressor Diffuse large B-cell lymphoma NF-kβ signaling In vitro [79]
  Tumor suppressor Sarcoma NF-kβ signaling In vitro [80]

3. UPS Inhibitors in Cancer therapy

The progress in targeting the UPS has been slow and this delay has been attributed to the following reasons. First, most components of the ubiquitin system do not possess a well-defined catalytic pocket to allow binding of small inhibitors. Second, the ubiquitination process relies on the dynamic rearrangement of multiple protein–protein interactions that traditionally have been challenging to disrupt with small molecule inhibitors. Third, components of the UPS are shown to possess both oncogenic and tumor suppressor properties due to the complexity of their regulatory cellular processes. Despite these challenges, components of the UPS have been considered as attractive targets for cancer treatment. In the following sections, we introduce some inhibitors against components of the UPS that have been tested in preclinical and clinical studies as summarized in Table 3.

Table 3. Summary of UPS inhibitors which are FDA-approved and/or tested in clinical trials described in this review.

Inhibitor Target Cancer Type Clinical Trial Reference
Bortezomib Proteasomal inhibitor Multiple myeloma, Mantle cell lymphoma, Leukemia, Neuroblastoma,
Head and Neck, Thyroid, Hepatocellular		 FDA approved www.clinicaltrials.gov
[81][82][83][84][85][86][87][88]
Carfilzomib Proteasomal inhibitor Multiple myeloma, Lymphoma, Relapsed and/or refractory multiple myeloma,
Leukemia, Lung, Thyroid, Refractory renal cell carcinoma		 FDA approved www.clinicaltrials.gov
[52][89][90][91][92][88]
Ixazomib Proteasomal inhibitor Multiple myeloma, Relapsed and/or refractory multiple myeloma, Lymphoma,
Leukemia, Breast, Glioblastoma, Renal cell carcinoma, Hodgkin and T cell
lymphoma		 FDA approved www.clinicaltrials.gov
[93]
Delanzomib Proteasomal inhibitor Non-Hodgkin’s lymphoma Phase I www.clinicaltrials.gov
Marizomib Proteasomal inhibitor Multiple myeloma, Advanced solid tumors Phase I/II www.clinicaltrials.gov
Oprozomib Proteasomal inhibitor Multiple myeloma, Glioma, Pancreatic, Lung, Melanoma, Lymphoma, Glipblastoma Phase I/II/III www.clinicaltrials.gov
MLN4924 NAE and UBA1(E1) Advanced malignant solid tumors, Melanoma, Hepatocellular, B cell lymphoma,
Hematologic malignancies, Acute myelocytic leukemia		 Phase I/II/III www.clinicaltrials.gov
TAK981 SAE (E1) B cell lymphoma, colorectal, non-Hodgkin’s, Advcnced/metasiatic solid tumors Phase I/II www.clinicaltrials.gov
TAS4464 NAE (E1) Multiple myeloma, non-Hodgkin lymphoma Phase I/II www.clinicaltrials.gov
SAR-405838 MDM2 (E2) Solid tumors Phase I www.clinicaltrials.gov
[87][94]
CGM-097 MDM2 (E2) Advanced p53 wildtype solid tumors Phase I www.clinicaltrials.gov
[95][96]
DS-3032b MDM2 (E2) Acute myelocytic leukemia Phase I/II www.clinicaltrials.gov
[97][98]
Debio1143 (AT-406) cIAP1/2 (E3) Acute myeloid leukemia Phase I www.clinicaltrials.gov
[99]
LC-161 IAP (E3) Advanced solid tumors Phase I www.clinicaltrials.gov
[100]
Birinapant IAP (E3) Solid tumors Phase I/II www.clinicaltrials.gov
[101]
Pimozide USP1 Glioma, Non-small cell lung cancer FDA approced for Tourette’s syndrome; Preclinical [102][103]
Mitoxantrone USP11 Metastatic crastrate -resistant prostate, Acute myeloid leukemia, Advanced breast cancer,
non-Hodgkin’s lymphoma, Primary liver		 FDA approved [104][105][106][107][108][109][110][111][112]

4. Conclusion

Frequent aberrant UPS activity seen in human malignancies indicate that the proteasome and components of the UPS are attractive therapeutic targets. Targeting the proteasome, in the clinic, has achieved success with FDA-approved proteasome inhibitors such as bortezomib, carfilzomib and ixazomib. Being the last step in the UPS, the use of proteasome inhibitors has shown undesirable side-effects arising from the action of up-stream UPS components. This shows that there is an untapped potential for the devel-opment of drugs against other components of the UPS. Thus, ubiquitin activating steps, E2, E3 and DUBs can be exploited for inhibition [113][114]. Unfortunately, most of these inhibitors show good efficacy in culture models but less so in animal models and clinical trials [115][116][117]. Traditionally, the ubiquitin activating steps and degradation possess the greatest potential due to presence of well-defined activity pockets but face issues of substrate specificity. The other UPS components however do not possess defined pockets for targeting with small inhibitors. Hence, delay in the development of successful UPS inhibitors can be attributed to the lack of knowledge of target protein structures and identifiable activity pockets for inhibitor binding. Advances in technology such as computer-aided design, mass spectrophotometry and high throughput screening may aid in the identification of suitable candidates. Further, the occurrence of oncogenic signaling together with aberrant UPS activity may affect the success of future UPS inhibitors. Nevertheless, a greater effort is required to elucidate the functions of aberrant UPS at both preclinical and clinical levels to better understand their roles in human malignancies to develop alternative paradigms for therapeutic intervention.  

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