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Ubiquitin: What It Is and Its Role in Targeted Cancer...
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Ubiquitin: What It Is and Its Role in Targeted Cancer Therapy

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 23419

Special Issue Editor

Prof. Dr. Jerry Vriend

E-Mail Website
Guest Editor
Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
Interests: medulloblastoma; melatonin; ubiquitin; cancer

Special Issue Information

Dear Colleagues

The ubiquitin proteasome system regulates the activity of many proteins in cells. Ubiquitin is added to proteins by a three-step process sequentially involving ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases (E3). While initial studies related the UPS to its role in degradation of damaged or excess proteins, the UPS has since been shown to be involved in many cellular processes, including transcription. Ubiquitin may be removed from proteins, and ubiquitin chains edited by deubiquitinases, as needed. Disease may result from genetic or physiological dysregulation of the proteasome, dysregulation of ubiquitin conjugases, dysregulation of ubiquitin ligases, dysregulation of specific E3 adaptors, or dysregulation of deubiquitinases.
Various components of the UPS have been shown to have some role in a variety of cancers. While regulation of the cell cycle may be a common theme relating the ubiquitin proteasome pathway to many cancers, additional themes relating the UPS to cancer include control of apoptosis, epigenetics, control of immunity and the immunoproteasome, and regulation of DNA damage repair. A well-documented example of a ubiquitin E3 ligase involved in cancer is BRCA1. A ubiquitin ligase complex important in regulation of the cell cycle is the Anaphase Promoting complex/cyclosome (APC/c).
In this Special Issue, we are interested in original research and/or reviews on the role of the ubiquitin proteasome system in transformation, invasiveness, proliferation, and maintenance of various cancer cells. From a practical point of view, ubiquitin ligases and their adaptors provide a large number of therapeutic targets, most of which remain unidentified. The challenge is to identify them and to engineer small specific molecular inhibitors which alone, or in conjunction with chemotherapeutic agents, improve the outcome of cancers. Thus, we are interested in novel therapeutic approaches including the use of neddylation inhibitors and PROTAC techniques making use of ubiquitin ligases.

Prof. Dr. Jerry Vriend
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Published Papers (8 papers)

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Editorial

Jump to: Research, Review

3 pages, 176 KiB  
Editorial
Role of Ubiquitin Ligases and Conjugases in Targeted Cancer Therapy
by Jerry Vriend
Cancers 2023, 15(13), 3460; https://doi.org/10.3390/cancers15133460 - 1 Jul 2023
Viewed by 986
Abstract
The ubiquitin proteasome system regulates the activity of many short-lived proteins in cells [...] Full article
(This article belongs to the Special Issue Ubiquitin: What It Is and Its Role in Targeted Cancer Therapy)

Research

Jump to: Editorial, Review

15 pages, 5208 KiB  
Article
AtomNet-Aided OTUD7B Inhibitor Discovery and Validation
by Jianfeng Chen, Derek L. Bolhuis, Christian Laggner, Deyu Kong, Le Yu, Xiaodong Wang, Michael J. Emanuele, Nicholas G. Brown and Pengda Liu
Cancers 2023, 15(2), 517; https://doi.org/10.3390/cancers15020517 - 14 Jan 2023
Cited by 10 | Viewed by 2557
Abstract
Protein deubiquitinases play critical pathophysiological roles in cancer. Among all deubiquitinases, an oncogenic function for OTUD7B has been established in genetic NSCLC murine models. However, few deubiquitinase inhibitors have been developed due to technical challenges. Here, we report a putative small molecule OTUD7B [...] Read more.
Protein deubiquitinases play critical pathophysiological roles in cancer. Among all deubiquitinases, an oncogenic function for OTUD7B has been established in genetic NSCLC murine models. However, few deubiquitinase inhibitors have been developed due to technical challenges. Here, we report a putative small molecule OTUD7B inhibitor obtained from an AI-aided screen of a 4 million compound library. We validated the effects of the OTUD7B inhibitor (7Bi) in reducing Akt-pS473 signals in multiple NSCLC and HEK293 cells by blocking OTUD7B-governed GβL deubiquitination in cells, as well as inhibiting OTUD7B-mediated cleavage of K11-linked di-ub in an in vitro enzyme assay. Furthermore, we report in leukemia cells, either genetic depletion or 7Bi-mediated pharmacological inhibition of OTUD7B reduces Akt-pS473 via inhibiting the OTUD7B/GβL signaling axis. Together, our study identifies the first putative OTUD7B inhibitor showing activities both in cells and in vitro, with promising applications as a therapeutic agent in treating cancer with OTUD7B overexpression. Full article
(This article belongs to the Special Issue Ubiquitin: What It Is and Its Role in Targeted Cancer Therapy)
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20 pages, 4769 KiB  
Article
The Emerging Role of E3 Ubiquitin Ligase SMURF2 in the Regulation of Transcriptional Co-Repressor KAP1 in Untransformed and Cancer Cells and Tissues
by Pooja Anil Shah, Sandy Boutros-Suleiman, Andrea Emanuelli, Biagio Paolini, Gal Levy-Cohen and Michael Blank
Cancers 2022, 14(7), 1607; https://doi.org/10.3390/cancers14071607 - 22 Mar 2022
Cited by 3 | Viewed by 3718
Abstract
KAP1 is an essential nuclear factor acting as a scaffold for protein complexes repressing transcription. KAP1 plays fundamental role in normal and cancer cell biology, affecting cell proliferation, DNA damage response, genome integrity maintenance, migration and invasion, as well as anti-viral and immune [...] Read more.
KAP1 is an essential nuclear factor acting as a scaffold for protein complexes repressing transcription. KAP1 plays fundamental role in normal and cancer cell biology, affecting cell proliferation, DNA damage response, genome integrity maintenance, migration and invasion, as well as anti-viral and immune response. Despite the foregoing, the mechanisms regulating KAP1 cellular abundance are poorly understood. In this study, we identified the E3 ubiquitin ligase SMURF2 as an important regulator of KAP1. We show that SMURF2 directly interacts with KAP1 and ubiquitinates it in vitro and in the cellular environment in a catalytically-dependent manner. Interestingly, while in the examined untransformed cells, SMURF2 mostly exerted a negative impact on KAP1 expression, a phenomenon that was also monitored in certain Smurf2-ablated mouse tissues, in tumor cells SMURF2 stabilized KAP1. This stabilization relied on the unaltered E3 ubiquitin ligase function of SMURF2. Further investigations showed that SMURF2 regulates KAP1 post-translationally, interfering with its proteasomal degradation. The conducted immunohistochemical studies showed that the reciprocal relationship between the expression of SMURF2 and KAP1 also exists in human normal and breast cancer tissues and suggested that this relationship may be disrupted by the carcinogenic process. Finally, through stratifying KAP1 interactome in cells expressing either SMURF2 wild-type or its E3 ligase-dead form, we demonstrate that SMURF2 has a profound impact on KAP1 protein–protein interactions and the associated functions, adding an additional layer in the SMURF2-mediated regulation of KAP1. Cumulatively, these findings uncover SMURF2 as a novel regulator of KAP1, governing its protein expression, interactions, and functions. Full article
(This article belongs to the Special Issue Ubiquitin: What It Is and Its Role in Targeted Cancer Therapy)
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15 pages, 1213 KiB  
Article
Characterization of the pVHL Interactome in Human Testis Using High-Throughput Library Screening
by Antonella Falconieri, Giovanni Minervini, Federica Quaglia, Geppo Sartori and Silvio C. E. Tosatto
Cancers 2022, 14(4), 1009; https://doi.org/10.3390/cancers14041009 - 17 Feb 2022
Cited by 1 | Viewed by 2397
Abstract
Functional impairment of the von Hippel–Lindau tumor suppressor (pVHL) is causative of a familiar increased risk of developing cancer. As an E3 substrate recognition particle, pVHL marks the hypoxia inducible factor 1α (HIF-1α) for degradation in normoxic conditions, thus acting as a key [...] Read more.
Functional impairment of the von Hippel–Lindau tumor suppressor (pVHL) is causative of a familiar increased risk of developing cancer. As an E3 substrate recognition particle, pVHL marks the hypoxia inducible factor 1α (HIF-1α) for degradation in normoxic conditions, thus acting as a key regulator of both acute and chronic cell adaptation to hypoxia. The male mice model carrying VHL gene conditional knockout presents significant abnormalities in testis development paired with defects in spermatogenesis and infertility, indicating that pVHL exerts testis-specific roles. Here we aimed to explore whether pVHL could have a similar role in humans by performing a testis-tissue library screening complemented with in-depth bioinformatics analysis. We identified 55 novel pVHL binding proteins directly involved in spermatogenesis, cell differentiation and reproductive metabolism. In addition, computational investigation of these new interactors identified multiple pVHL-specific binding motifs and demonstrated that somatic mutations described in human cancers reside in these binding regions. Collectively, these findings suggest that, in addition to its role in cancer formation, pVHL may also be pivotal in normal gonadal development in humans. Full article
(This article belongs to the Special Issue Ubiquitin: What It Is and Its Role in Targeted Cancer Therapy)
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19 pages, 6977 KiB  
Article
A Novel Signature of CCNF-Associated E3 Ligases Collaborate and Counter Each Other in Breast Cancer
by Shu-Chun Chang, Chin-Sheng Hung, Bo-Xiang Zhang, Tsung-Han Hsieh, Wayne Hsu and Jeak Ling Ding
Cancers 2021, 13(12), 2873; https://doi.org/10.3390/cancers13122873 - 8 Jun 2021
Cited by 16 | Viewed by 3132
Abstract
Breast cancer (BRCA) malignancy causes major fatalities amongst women worldwide. SCF (Skp1-cullin-F-box proteins) E3 ubiquitin ligases are the most well-known members of the ubiquitination–proteasome system (UPS), which promotes cancer initiation and progression. Recently, we demonstrated that FBXL8, a novel F-box protein (SCFF-boxes [...] Read more.
Breast cancer (BRCA) malignancy causes major fatalities amongst women worldwide. SCF (Skp1-cullin-F-box proteins) E3 ubiquitin ligases are the most well-known members of the ubiquitination–proteasome system (UPS), which promotes cancer initiation and progression. Recently, we demonstrated that FBXL8, a novel F-box protein (SCFF-boxes) of SCF E3 ligase, accelerates BRCA advancement and metastasis. Since SCFF-boxes is a key component of E3 ligases, we hypothesized that other SCFF-boxes besides FBXL8 probably collaborate in regulating breast carcinogenesis. In this study, we retrospectively profiled the transcriptome of BRCA tissues and found a notable upregulation of four SCFF-box E3 ligases (FBXL8, FBXO43, FBXO15, and CCNF) in the carcinoma tissues. Similar to FBXL8, the knockdown of FBXO43 reduced cancer cell viability and proliferation, suggesting its pro-tumorigenic role. The overexpression of CCNF inhibited cancer cell progression, indicating its anti-tumorigenic role. Unexpectedly, CCNF protein was markedly downregulated in BRCA tissues, although its mRNA level was high. We showed that both E3 ligases, FBXL8 and FZR1, pulled down CCNF. Double knockdown of FBXL8 and FZR1 caused CCNF accumulation. On the other hand, CCNF itself pulled down a tumorigenic factor, RRM2, and CCNF overexpression reduced RRM2. Altogether, we propose a signature network of E3 ligases that collaboratively modulates CCNF anti-cancer activity. There is potential to target BRCA through modulation of the partnership axes of (i) CCNF-FBXL8, (ii) CCNF-FZR1, and (iii) CCNF-RRM2, particularly, via CCNF overexpression and activation and FBXL8/FZR1 suppression. Full article
(This article belongs to the Special Issue Ubiquitin: What It Is and Its Role in Targeted Cancer Therapy)
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Review

Jump to: Editorial, Research

27 pages, 1558 KiB  
Review
Autophagy/Mitophagy Regulated by Ubiquitination: A Promising Pathway in Cancer Therapeutics
by Seung-Cheol Jee and Heesun Cheong
Cancers 2023, 15(4), 1112; https://doi.org/10.3390/cancers15041112 - 9 Feb 2023
Cited by 10 | Viewed by 3259
Abstract
Autophagy is essential for organismal development, maintenance of energy homeostasis, and quality control of organelles and proteins. As a selective form of autophagy, mitophagy is necessary for effectively eliminating dysfunctional mitochondria. Both autophagy and mitophagy are linked with tumor progression and inhibition. The [...] Read more.
Autophagy is essential for organismal development, maintenance of energy homeostasis, and quality control of organelles and proteins. As a selective form of autophagy, mitophagy is necessary for effectively eliminating dysfunctional mitochondria. Both autophagy and mitophagy are linked with tumor progression and inhibition. The regulation of mitophagy and autophagy depend upon tumor type and stage. In tumors, mitophagy has dual roles: it removes damaged mitochondria to maintain healthy mitochondria and energy production, which are necessary for tumor growth. In contrast, mitophagy has been shown to inhibit tumor growth by mitigating excessive ROS production, thus preventing mutation and chromosomal instability. Ubiquitination and deubiquitination are important modifications that regulate autophagy. Multiple E3 ubiquitin ligases and DUBs modulate the activity of the autophagy and mitophagy machinery, thereby influencing cancer progression. In this review, we summarize the mechanistic association between cancer development and autophagy/mitophagy activities regulated by the ubiquitin modification of autophagic proteins. In addition, we discuss the function of multiple proteins involved in autophagy/mitophagy in tumors that may represent potential therapeutic targets. Full article
(This article belongs to the Special Issue Ubiquitin: What It Is and Its Role in Targeted Cancer Therapy)
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27 pages, 1626 KiB  
Review
The E3 Ligases in Cervical Cancer and Endometrial Cancer
by Fengguang Zhai, Jie Wang, Weili Yang, Meng Ye and Xiaofeng Jin
Cancers 2022, 14(21), 5354; https://doi.org/10.3390/cancers14215354 - 30 Oct 2022
Cited by 14 | Viewed by 2755
Abstract
Endometrial (EC) and cervical (CC) cancers are the most prevalent malignancies of the female reproductive system. There is a global trend towards increasing incidence and mortality, with a decreasing age trend. E3 ligases label substrates with ubiquitin to regulate their activity and stability [...] Read more.
Endometrial (EC) and cervical (CC) cancers are the most prevalent malignancies of the female reproductive system. There is a global trend towards increasing incidence and mortality, with a decreasing age trend. E3 ligases label substrates with ubiquitin to regulate their activity and stability and are involved in various cellular functions. Studies have confirmed abnormal expression or mutations of E3 ligases in EC and CC, indicating their vital roles in the occurrence and progression of EC and CC. This paper provides an overview of the E3 ligases implicated in EC and CC and discusses their underlying mechanism. In addition, this review provides research advances in the target of ubiquitination processes in EC and CC. Full article
(This article belongs to the Special Issue Ubiquitin: What It Is and Its Role in Targeted Cancer Therapy)
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22 pages, 3172 KiB  
Review
Ubiquitin Proteasome Pathway Transcriptome in Epithelial Ovarian Cancer
by Jerry Vriend and Mark W. Nachtigal
Cancers 2021, 13(11), 2659; https://doi.org/10.3390/cancers13112659 - 28 May 2021
Cited by 7 | Viewed by 3295
Abstract
In this article, we reviewed the transcription of genes coding for components of the ubiquitin proteasome pathway in publicly available datasets of epithelial ovarian cancer (EOC). KEGG analysis was used to identify the major pathways distinguishing EOC of low malignant potential (LMP) from [...] Read more.
In this article, we reviewed the transcription of genes coding for components of the ubiquitin proteasome pathway in publicly available datasets of epithelial ovarian cancer (EOC). KEGG analysis was used to identify the major pathways distinguishing EOC of low malignant potential (LMP) from invasive high-grade serous ovarian carcinomas (HGSOC), and to identify the components of the ubiquitin proteasome system that contributed to these pathways. We identified elevated transcription of several genes encoding ubiquitin conjugases associated with HGSOC. Fifty-eight genes coding for ubiquitin ligases and more than 100 genes encoding ubiquitin ligase adaptors that were differentially expressed between LMP and HGSOC were also identified. Many differentially expressed genes encoding E3 ligase adaptors were Cullin Ring Ligase (CRL) adaptors, and 64 of them belonged to the Cullin 4 DCX/DWD family of CRLs. The data suggest that CRLs play a role in HGSOC and that some of these proteins may be novel therapeutic targets. Differential expression of genes encoding deubiquitinases and proteasome subunits was also noted. Full article
(This article belongs to the Special Issue Ubiquitin: What It Is and Its Role in Targeted Cancer Therapy)
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