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Cancers
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Ubiquitin-Related Cancer
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Ubiquitin-Related Cancer

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 18698

Special Issue Editor

Dr. Paul Galardy

E-Mail Website
Guest Editor
Division of Pediatric Hematology-Oncology, Mayo Clinic, 200 First St. SW, Guggenheim 15, Rochester, MN, 55905, USA
Interests: ubiquitin-proteasome system; cancer pathogenesis

Special Issue Information

Dear Colleagues,

Knowledge of ubiquitin (Ub) has dramatically evolved from that of a molecular tag that directs proteasome degradation to that of an important cell-signaling molecule that orchestrates the activity of myriad cellular pathways. Ub modification serves important and at times essential roles in nearly all cellular events, with many at the center of the biology of cancer. Key roles in events that span the distance from the cell surface to the chromatin and back place Ub in a key position to influence many of the hallmarks of cancer. This notion becomes even more complex when one considers ubiquitin-like proteins (UbLs) and the increasing recognition of their roles in malignancy. Ongoing research has now uncovered roles for Ub and Ub(L) conjugating and deconjugating enzymes as oncogenes, non-oncogenes, and tumor suppressor genes. With the unraveling of the role of Ub and UbLs in cancer, there has been a growing interest in the development of small-molecule inhibitors targeting enzymes in these pathways to be used as novel anti-neoplastic agents.

The FDA and EMA approval and subsequent success of the first in class proteasome inhibitor bortezomib served as proof of principle that these pathways are important as cancer targets. The proteasome, of course, is only one component of the ubiquitin economy and targeting individual steps in the pathway may offer much greater specificity and efficacy. The enzymatic steps involved in the addition and removal of Ub(L)s to targets have been relatively well characterized. The addition side of the equation involves a three-step process involving activating enzymes (E1s), conjugating enzymes (E2s), and ligases (E3s). The deconjugation of Ub(Ls) is catalyzed by a set of enzymes that cleave the isopeptide bond (isopeptidases) between the Ub(L) and substrates. The E1, E2, some E3s, and most Ub(L) isopeptidases require an active-site cysteine, whereas some isopeptidases are metalloproteases.

Existing medications such as thalidomide and its derivatives that target the Ub E3 ligase cereblon have demonstrated the therapeutic potential of selective E3 ligase inhibition in cancer. New inhibitors of the conjugation of Ub and UbLs to cellular targets are under clinical development, with the NEDD8-activating enzyme inhibitor MLN4924 (Pevonedistat) involved in 34 clinical trials at various stages of enrollment and inhibitors for the ubiquitin and SUMO (small ubiquitin-like modifier) activating enzymes also in the pipeline. We are just beginning to develop and study the potential efficacy of Ub(L) isopeptidase inhibitors as potential therapeutics.

This Special Issue of Cancers on “Ubiquitin-Related Cancer” will cover the involvement of Ub(L)s and the enzymes involved in their attachment and removal to substrates in cancer development, progression, and therapy resistance, and as targets of therapy to consolidate and further stimulate work in these fields.

Dr. Paul Galardy
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Ubiquitin
  • Cancer
  • SUMO
  • Nedd8
  • ISG15
  • E3 ligase
  • E2 conjugating enzyme
  • E1 activating enzyme
  • Isopeptidase
  • Deubiquitinating enzyme
  • DUB

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Published Papers (5 papers)

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Research

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14 pages, 7109 KiB  
Article
USP22 Suppresses SPARC Expression in Acute Colitis and Inflammation-Associated Colorectal Cancer
by Robyn Laura Kosinsky, Dominik Saul, Christoph Ammer-Herrmenau, William A. Faubion, Albrecht Neesse and Steven A. Johnsen
Cancers 2021, 13(8), 1817; https://doi.org/10.3390/cancers13081817 - 10 Apr 2021
Cited by 14 | Viewed by 3261
Abstract
As a member of the 11-gene “death-from-cancer” gene expression signature, ubiquitin-specific protease 22 (USP22) has been considered an oncogene in various human malignancies, including colorectal cancer (CRC). We recently identified an unexpected tumor-suppressive function of USP22 in CRC and detected intestinal inflammation after [...] Read more.
As a member of the 11-gene “death-from-cancer” gene expression signature, ubiquitin-specific protease 22 (USP22) has been considered an oncogene in various human malignancies, including colorectal cancer (CRC). We recently identified an unexpected tumor-suppressive function of USP22 in CRC and detected intestinal inflammation after Usp22 deletion in mice. We aimed to investigate the function of USP22 in intestinal inflammation as well as inflammation-associated CRC. We evaluated the effects of a conditional, intestine-specific knockout of Usp22 during dextran sodium sulfate (DSS)-induced colitis and in a model for inflammation-associated CRC. Mice were analyzed phenotypically and histologically. Differentially regulated genes were identified in USP22-deficient human CRC cells and the occupancy of active histone markers was determined using chromatin immunoprecipitation. The knockout of Usp22 increased inflammation-associated symptoms after DSS treatment locally and systemically. In addition, Usp22 deletion resulted in increased inflammation-associated colorectal tumor growth. Mechanistically, USP22 depletion in human CRC cells induced a profound upregulation of secreted protein acidic and rich in cysteine (SPARC) by affecting H3K27ac and H2Bub1 occupancy on the SPARC gene. The induction of SPARC was confirmed in vivo in our intestinal Usp22-deficient mice. Together, our findings uncover that USP22 controls SPARC expression and inflammation intensity in colitis and CRC. Full article
(This article belongs to the Special Issue Ubiquitin-Related Cancer)
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19 pages, 5251 KiB  
Article
The Mitochondrial Protease LonP1 Promotes Proteasome Inhibitor Resistance in Multiple Myeloma
by Laure Maneix, Melanie A. Sweeney, Sukyeong Lee, Polina Iakova, Shannon E. Moree, Ergun Sahin, Premal Lulla, Sarvari V. Yellapragada, Francis T. F. Tsai and Andre Catic
Cancers 2021, 13(4), 843; https://doi.org/10.3390/cancers13040843 - 17 Feb 2021
Cited by 13 | Viewed by 4267
Abstract
Multiple myeloma and its precursor plasma cell dyscrasias affect 3% of the elderly population in the US. Proteasome inhibitors are an essential part of several standard drug combinations used to treat this incurable cancer. These drugs interfere with the main pathway of protein [...] Read more.
Multiple myeloma and its precursor plasma cell dyscrasias affect 3% of the elderly population in the US. Proteasome inhibitors are an essential part of several standard drug combinations used to treat this incurable cancer. These drugs interfere with the main pathway of protein degradation and lead to the accumulation of damaged proteins inside cells. Despite promising initial responses, multiple myeloma cells eventually become drug resistant in most patients. The biology behind relapsed/refractory multiple myeloma is complex and poorly understood. Several studies provide evidence that in addition to the proteasome, mitochondrial proteases can also contribute to protein quality control outside of mitochondria. We therefore hypothesized that mitochondrial proteases might counterbalance protein degradation in cancer cells treated with proteasome inhibitors. Using clinical and experimental data, we found that overexpression of the mitochondrial matrix protease LonP1 (Lon Peptidase 1) reduces the efficacy of proteasome inhibitors. Some proteasome inhibitors partially crossinhibit LonP1. However, we show that the resistance effect of LonP1 also occurs when using drugs that do not block this protease, suggesting that LonP1 can compensate for loss of proteasome activity. These results indicate that targeting both the proteasome and mitochondrial proteases such as LonP1 could be beneficial for treatment of multiple myeloma. Full article
(This article belongs to the Special Issue Ubiquitin-Related Cancer)
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21 pages, 4279 KiB  
Article
Human FBXL8 Is a Novel E3 Ligase Which Promotes BRCA Metastasis by Stimulating Pro-Tumorigenic Cytokines and Inhibiting Tumor Suppressors
by Shu-Chun Chang, Wayne Hsu, Emily Chia-Yu Su, Chin-Sheng Hung and Jeak Ling Ding
Cancers 2020, 12(8), 2210; https://doi.org/10.3390/cancers12082210 - 7 Aug 2020
Cited by 12 | Viewed by 2780
Abstract
The initiation and progression of breast cancer (BRCA) is associated with inflammation and immune-overactivation, which is critically modulated by the E3 ubiquitin ligase. However, the underlying mechanisms and key factors involved in BRCA formation and disease advancement remains under-explored. By retrospective studies of [...] Read more.
The initiation and progression of breast cancer (BRCA) is associated with inflammation and immune-overactivation, which is critically modulated by the E3 ubiquitin ligase. However, the underlying mechanisms and key factors involved in BRCA formation and disease advancement remains under-explored. By retrospective studies of BRCA patient tissues; and gene knockdown and gain/loss-of-function studies, we uncovered a novel E3 ligase, FBXL8, in BRCA. A signature expression profile of F-box factors that specifically target and degrade proteins involved in cell death/survival, was identified. FBXL8 emerged as a prominent member of the F-box factors. Ex vivo analysis of 1349 matched BRCA tissues indicated that FBXL8 promotes cell survival and tumorigenesis, and its level escalates with BRCA progression. Knockdown of FBXL8 caused: (i) intrinsic apoptosis, (ii) inhibition of cell migration and invasion, (iii) accumulation of two tumor-suppressors, CCND2 and IRF5, and (iv) downregulation of cancer-promoting cytokines/chemokines; all of which curtailed the tumor microenvironment and displayed potential to suppress cancer progression. Co-IP study suggests that two tumor-suppressors, CCND2 and IRF5 are part of the immune-complex of FBXL8. The protein levels of CCND2 and IRF5 inversely correlated with FBXL8 expression, implying that FBXL8 E3 ligase was associated with the degradation of CCND2 and IRF5. Altogether, we propose the exploitation of the ubiquitin signaling axis of FBXL8-CCND2-IRF5 for anti-cancer strategies and potential therapeutics. Full article
(This article belongs to the Special Issue Ubiquitin-Related Cancer)
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20 pages, 3036 KiB  
Review
Ubiquitin and Ubiquitin-Like Proteins Are Essential Regulators of DNA Damage Bypass
by Nicole A. Wilkinson, Katherine S. Mnuskin, Nicholas W. Ashton and Roger Woodgate
Cancers 2020, 12(10), 2848; https://doi.org/10.3390/cancers12102848 - 2 Oct 2020
Cited by 4 | Viewed by 3920
Abstract
Many endogenous and exogenous factors can induce genomic instability in human cells, in the form of DNA damage and mutations, that predispose them to cancer development. Normal cells rely on DNA damage bypass pathways such as translesion synthesis (TLS) and template switching (TS) [...] Read more.
Many endogenous and exogenous factors can induce genomic instability in human cells, in the form of DNA damage and mutations, that predispose them to cancer development. Normal cells rely on DNA damage bypass pathways such as translesion synthesis (TLS) and template switching (TS) to replicate past lesions that might otherwise result in prolonged replication stress and lethal double-strand breaks (DSBs). However, due to the lower fidelity of the specialized polymerases involved in TLS, the activation and suppression of these pathways must be tightly regulated by post-translational modifications such as ubiquitination in order to limit the risk of mutagenesis. Many cancer cells rely on the deregulation of DNA damage bypass to promote carcinogenesis and tumor formation, often giving them heightened resistance to DNA damage from chemotherapeutic agents. In this review, we discuss the key functions of ubiquitin and ubiquitin-like proteins in regulating DNA damage bypass in human cells, and highlight ways in which these processes are both deregulated in cancer progression and might be targeted in cancer therapy. Full article
(This article belongs to the Special Issue Ubiquitin-Related Cancer)
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17 pages, 2433 KiB  
Review
Ubiquilin Networking in Cancers
by Salinee Jantrapirom, Luca Lo Piccolo, Dumnoensun Pruksakorn, Saranyapin Potikanond and Wutigri Nimlamool
Cancers 2020, 12(6), 1586; https://doi.org/10.3390/cancers12061586 - 15 Jun 2020
Cited by 12 | Viewed by 3796
Abstract
Ubiquilins or UBQLNs, members of the ubiquitin-like and ubiquitin-associated domain (UBL-UBA) protein family, serve as adaptors to coordinate the degradation of specific substrates via both proteasome and autophagy pathways. The UBQLN substrates reveal great diversity and impact a wide range of cellular functions. [...] Read more.
Ubiquilins or UBQLNs, members of the ubiquitin-like and ubiquitin-associated domain (UBL-UBA) protein family, serve as adaptors to coordinate the degradation of specific substrates via both proteasome and autophagy pathways. The UBQLN substrates reveal great diversity and impact a wide range of cellular functions. For decades, researchers have been attempting to uncover a puzzle and understand the role of UBQLNs in human cancers, particularly in the modulation of oncogene’s stability and nucleotide excision repair. In this review, we summarize the UBQLNs’ genetic variants that are associated with the most common cancers and also discuss their reliability as a prognostic marker. Moreover, we provide an overview of the UBQLNs networks that are relevant to cancers in different ways, including cell cycle, apoptosis, epithelial-mesenchymal transition, DNA repairs and miRNAs. Finally, we include a future prospective on novel ubiquilin-based cancer therapies. Full article
(This article belongs to the Special Issue Ubiquitin-Related Cancer)
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