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The Role of the Ubiquitin-Proteasome-System in Human Cancer
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The Role of the Ubiquitin-Proteasome-System in Human Cancer

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

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 57280

Special Issue Editor

Dr. Tarek Abbas

E-Mail Website
Guest Editor
Department of Radiation Oncology, University of Virginia, 1300 Jefferson Park Avenue, Charlottesville, VA, USA
Interests: genomic instability and human cancer; ubiquitin-dependent regulation of DNA replication; cellular responses to DNA damage; DNA damage repair
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Deregulation of protein ubiquitination underlies the development of an increasing number of human diseases, including cancer. Several ubiquitin ligases and ligase adaptors as well as deubiquitinating enzymes are mutated, or their expression deregulated, in a large number of human malignancies, suggesting that they may play a significant role in the initiation and progression of human cancer and may additionally modulate the cancer sensitivity to conventional chemo- and radiotherapy. Furthermore, a large number of tumor suppressor proteins and tumor oncoproteins are targets of the ubiquitin system, and point mutations in the genes encoding for these proteins interfere with their regulated ubiquitin-dependent proteolysis leading to their repressed or enhanced activity.

We are particularly interested in papers that report on the identification and/or characterization of novel ubiquitin regulating proteins and enzymes specifically involved in the regulation of mammalian DNA replication, cell cycle control, DNA damage sensing and repair, and cellular apoptosis and may, therefore, be particularly relevant to the initiation and/or progression of human cancer and to their responses to currently available therapies. Papers that provide mechanistic understanding of the role of deregulated ubiquitination in the development of various human cancers or the development of resistance as well as the development of animal models of deregulated ubiquitin components to address their role in cancer or cancer therapy are highly encouraged. Moreover, papers leading to the development of specific methodologies aiming at better screening/identification for targets of the ubiquitin system underlying the development of specific human cancer would be of great interest. Reviews that summarize current knowledge regarding the role of the ubiquitin system in cancer and the development of new therapeutic modalities that depend on targeting the ubiquitin system or clinical trials with agents targeting the ubiquitin system would be particularly useful. Potential topics include, but are not limited to:

  • Novel ubiquitin pathways in specific cancers
  • Role of ubiquitination in cancer initiation and progression
  • Role of ubiquitination in cancer therapy and resistance
  • Genetic models of deregulated ubiquitination in cancer
  • Ubiquitination and tumor microenvironment
  • Methods of screening/identification of cancer-specific targets of the ubiquitin system
  • Rational design of agents targeting the ubiquitin system for cancer therapy

Prof. Dr. Tarek Abbas
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.

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
  • proteolysis, cancer
  • chemotherapy
  • radiotherapy
  • DNA damage

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Published Papers (13 papers)

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Research

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19 pages, 7767 KiB  
Article
HPVE6-USP46 Mediated Cdt2 Stabilization Reduces Set8 Mediated H4K20-Methylation to Induce Gene Expression Changes
by Shashi Kiran, Briana Wilson, Shekhar Saha, Julia Ann Graff and Anindya Dutta
Cancers 2022, 14(1), 30; https://doi.org/10.3390/cancers14010030 - 22 Dec 2021
Cited by 4 | Viewed by 3262
Abstract
E6 from high-risk strains of HPV is well known to transform cells by deregulating p53. We reported that in HPV transformed cell-lines E6 from high-risk HPV can recruit the USP46 deubiquitinase to substrates such as Cdt2 and stabilize the latter, and that USP46 [...] Read more.
E6 from high-risk strains of HPV is well known to transform cells by deregulating p53. We reported that in HPV transformed cell-lines E6 from high-risk HPV can recruit the USP46 deubiquitinase to substrates such as Cdt2 and stabilize the latter, and that USP46 is important for growth of HPV induced tumors in xenografts. Here we show that in cervical cancer biopsies the stabilization of Cdt2 in the HPV-induced cancers leads to the decrease of a CRL4-Cdt2 substrate, the histone H4K20 mono-methyltransferase Set8, and decrease in H4K20me1 or H4K20me3 that can be detected by immunohistochemistry. In HPV-transformed cancer cell lines in vitro, knockdown of E6 decreases Cdt2 and increases Set8. Co-knockdown of Set8 shows that some of the gene expression changes produced by E6 knockdown is due to the increase of Set8. EGFR and EGFR regulated genes were identified in this set of genes. Turning to the mechanism by which E6 stabilizes Cdt2, we find that a purified E6:USP46 complex has significantly more de-ubiquitinase activity in vitro than USP46 alone, demonstrating that E6 can directly interact with USP46 in the absence of other proteins and that it can substitute for the known activators of USP46, UAF1 and WDR20. Deletion mapping of Cdt2 shows that there are three discrete, but redundant, parts of the substrate that are essential for stabilization by E6: USP46. The helix–loop–helix region or the WD40 repeat driven beta-propeller structure of Cdt2 are dispensable for the stabilization implying that interaction with DDB1 (and the rest of the CRL4 complex) or with the substrate of the CRL4-Cdt2 E3 ligase is not necessary for E6:USP46 to interact with and stabilize Cdt2. The identification of 50 amino acid stretches in the 731 amino acid Cdt2 protein as being important for the stabilization by E6 underlines the specificity of the process. In summary, E6 activates the deubiquitinase activity of USP46, stabilizes Cdt2 utilizing multiple sites on Cdt2, and leads to degradation of Set8 and changes in gene-expression in HPV-transformed cells. Full article
(This article belongs to the Special Issue The Role of the Ubiquitin-Proteasome-System in Human Cancer)
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13 pages, 11850 KiB  
Article
Ubiquitin Specific Protease 29 Functions as an Oncogene Promoting Tumorigenesis in Colorectal Carcinoma
by Arun Pandian Chandrasekaran, Bharathi Suresh, Neha Sarodaya, Na-Re Ko, Seung-Jun Oh, Kye-Seong Kim and Suresh Ramakrishna
Cancers 2021, 13(11), 2706; https://doi.org/10.3390/cancers13112706 - 31 May 2021
Cited by 17 | Viewed by 3097
Abstract
Colorectal carcinoma is the third foremost cause of cancer-related deaths and accounts for 5.8% of all deaths globally. The molecular mechanisms of colon cancer progression and metastasis control are not well studied. Ubiquitin-specific protease 29 (USP29), a deubiquitinating enzyme, is involved in the [...] Read more.
Colorectal carcinoma is the third foremost cause of cancer-related deaths and accounts for 5.8% of all deaths globally. The molecular mechanisms of colon cancer progression and metastasis control are not well studied. Ubiquitin-specific protease 29 (USP29), a deubiquitinating enzyme, is involved in the occurrence and development of wide variety of cancers. However, its clinical significance and biological roles in colorectal carcinoma (CRC) remain unexplored. In this research, we observed that the rate of USP29 overexpression was higher in colon cancer patient tissues relative to its corresponding normal tissues. CRISPR-Cas9-mediated depletion of USP29 triggered DNA double strand breaks and delayed cell-cycle progression in HCT116 cells. We also demonstrated that USP29 depletion hampers the colony formation and increases apoptosis of HCT116 cells. USP29 knockdown significantly decreased CRC cell proliferation in vitro. Depletion of USP29 in HCT116 cells substantially reduced the tumor volume of mouse xenografts. In conclusion, our study shows that elevated expression of USP29 promotes malignancy in CRC, suggesting that USP29 could be a promising target for colon cancer therapy. Full article
(This article belongs to the Special Issue The Role of the Ubiquitin-Proteasome-System in Human Cancer)
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23 pages, 4192 KiB  
Article
Mapping of Genomic Vulnerabilities in the Post-Translational Ubiquitination, SUMOylation and Neddylation Machinery in Breast Cancer
by Jesús Fuentes-Antrás, Ana Lucía Alcaraz-Sanabria, Esther Cabañas Morafraile, María del Mar Noblejas-López, Eva María Galán-Moya, Mariona Baliu-Pique, Igor López-Cade, Vanesa García-Barberán, Pedro Pérez-Segura, Aránzazu Manzano, Atanasio Pandiella, Balázs Győrffy and Alberto Ocaña
Cancers 2021, 13(4), 833; https://doi.org/10.3390/cancers13040833 - 17 Feb 2021
Cited by 10 | Viewed by 3736
Abstract
The dysregulation of post-translational modifications (PTM) transversally impacts cancer hallmarks and constitutes an appealing vulnerability for drug development. In breast cancer there is growing preclinical evidence of the role of ubiquitin and ubiquitin-like SUMO and Nedd8 peptide conjugation to the proteome in tumorigenesis [...] Read more.
The dysregulation of post-translational modifications (PTM) transversally impacts cancer hallmarks and constitutes an appealing vulnerability for drug development. In breast cancer there is growing preclinical evidence of the role of ubiquitin and ubiquitin-like SUMO and Nedd8 peptide conjugation to the proteome in tumorigenesis and drug resistance, particularly through their interplay with estrogen receptor signaling and DNA repair. Herein we explored genomic alterations in these processes using RNA-seq and mutation data from TCGA and METABRIC datasets, and analyzed them using a bioinformatic pipeline in search of those with prognostic and predictive capability which could qualify as subjects of drug research. Amplification of UBE2T, UBE2C, and BIRC5 conferred a worse prognosis in luminal A/B and basal-like tumors, luminal A/B tumors, and luminal A tumors, respectively. Higher UBE2T expression levels were predictive of a lower rate of pathological complete response in triple negative breast cancer patients following neoadjuvant chemotherapy, whereas UBE2C and BIRC5 expression was higher in luminal A patients with tumor relapse within 5 years of endocrine therapy or chemotherapy. The transcriptomic signatures of USP9X and USP7 gene mutations also conferred worse prognosis in luminal A, HER2-enriched, and basal-like tumors, and in luminal A tumors, respectively. In conclusion, we identified and characterized the clinical value of a group of genomic alterations in ubiquitination, SUMOylation, and neddylation enzymes, with potential for drug development in breast cancer. Full article
(This article belongs to the Special Issue The Role of the Ubiquitin-Proteasome-System in Human Cancer)
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14 pages, 3356 KiB  
Article
The Giant HECT E3 Ubiquitin Ligase HERC1 Is Aberrantly Expressed in Myeloid Related Disorders and It Is a Novel BCR-ABL1 Binding Partner
by Muhammad Shahzad Ali, Cristina Panuzzo, Chiara Calabrese, Alessandro Maglione, Rocco Piazza, Daniela Cilloni, Giuseppe Saglio, Barbara Pergolizzi and Enrico Bracco
Cancers 2021, 13(2), 341; https://doi.org/10.3390/cancers13020341 - 19 Jan 2021
Cited by 7 | Viewed by 4343
Abstract
HERC E3 subfamily members are parts of the E3 ubiquitin ligases and key players for a wide range of cellular functions. Though the involvement of the Ubiquitin Proteasome System in blood disorders has been broadly studied, so far the role of large HERCs [...] Read more.
HERC E3 subfamily members are parts of the E3 ubiquitin ligases and key players for a wide range of cellular functions. Though the involvement of the Ubiquitin Proteasome System in blood disorders has been broadly studied, so far the role of large HERCs in this context remains unexplored. In the present study we examined the expression of the large HECT E3 Ubiquitin Ligase, HERC1, in blood disorders. Our findings revealed that HERC1 gene expression was severely downregulated both in acute and in chronic myelogenous leukemia at diagnosis, while it is restored after complete remission achievement. Instead, in Philadelphia the negative myeloproliferative neoplasm HERC1 level was peculiarly controlled, being very low in Primary Myelofibrosis and significantly upregulated in those Essential Thrombocytemia specimens harboring the mutation in the calreticulin gene. Remarkably, in CML cells HERC1 mRNA level was associated with the BCR-ABL1 kinase activity and the HERC1 protein physically interacted with BCR-ABL1. Furthermore, we found that HERC1 was directly tyrosine phosphorylated by the ABL kinase. Overall and for the first time, we provide original evidence on the potential tumor-suppressing or -promoting properties, depending on the context, of HERC1 in myeloid related blood disorders. Full article
(This article belongs to the Special Issue The Role of the Ubiquitin-Proteasome-System in Human Cancer)
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Review

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24 pages, 2291 KiB  
Review
Deubiquitinases in Cancers: Aspects of Proliferation, Metastasis, and Apoptosis
by Jiaqi LIU, Chi Tim LEUNG, Luyun LIANG, Yuqin WANG, Jian CHEN, Keng Po LAI and William Ka Fai TSE
Cancers 2022, 14(14), 3547; https://doi.org/10.3390/cancers14143547 - 21 Jul 2022
Cited by 17 | Viewed by 3861
Abstract
Deubiquitinases (DUBs) deconjugate ubiquitin (UBQ) from ubiquitylated substrates to regulate its activity and stability. They are involved in several cellular functions. In addition to the general biological regulation of normal cells, studies have demonstrated their critical roles in various cancers. In this review, [...] Read more.
Deubiquitinases (DUBs) deconjugate ubiquitin (UBQ) from ubiquitylated substrates to regulate its activity and stability. They are involved in several cellular functions. In addition to the general biological regulation of normal cells, studies have demonstrated their critical roles in various cancers. In this review, we evaluated and grouped the biological roles of DUBs, including proliferation, metastasis, and apoptosis, in the most common cancers in the world (liver, breast, prostate, colorectal, pancreatic, and lung cancers). The current findings in these cancers are summarized, and the relevant mechanisms and relationship between DUBs and cancers are discussed. In addition to highlighting the importance of DUBs in cancer biology, this study also provides updated information on the roles of DUBs in different types of cancers. Full article
(This article belongs to the Special Issue The Role of the Ubiquitin-Proteasome-System in Human Cancer)
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15 pages, 901 KiB  
Review
Protein Degradation by E3 Ubiquitin Ligases in Cancer Stem Cells
by Macarena Quiroga, Andrea Rodríguez-Alonso, Gloria Alfonsín, Juan José Escuder Rodríguez, Sara M. Breijo, Venancio Chantada and Angélica Figueroa
Cancers 2022, 14(4), 990; https://doi.org/10.3390/cancers14040990 - 16 Feb 2022
Cited by 5 | Viewed by 3604
Abstract
Cancer stem cells are a small subpopulation within the tumor with high capacity for self-renewal, differentiation and reconstitution of tumor heterogeneity. Cancer stem cells are major contributors of tumor initiation, metastasis and therapy resistance in cancer. Emerging evidence indicates that ubiquitination-mediated post-translational modification [...] Read more.
Cancer stem cells are a small subpopulation within the tumor with high capacity for self-renewal, differentiation and reconstitution of tumor heterogeneity. Cancer stem cells are major contributors of tumor initiation, metastasis and therapy resistance in cancer. Emerging evidence indicates that ubiquitination-mediated post-translational modification plays a fundamental role in the maintenance of cancer stem cell characteristics. In this review, we will discuss how protein degradation controlled by the E3 ubiquitin ligases plays a fundamental role in the self-renewal, maintenance and differentiation of cancer stem cells, highlighting the possibility to develop novel therapeutic strategies against E3 ubiquitin ligases targeting CSCs to fight cancer. Full article
(This article belongs to the Special Issue The Role of the Ubiquitin-Proteasome-System in Human Cancer)
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23 pages, 2866 KiB  
Review
The PRP19 Ubiquitin Ligase, Standing at the Cross-Roads of mRNA Processing and Genome Stability
by Mouhamed Idrissou and Alexandre Maréchal
Cancers 2022, 14(4), 878; https://doi.org/10.3390/cancers14040878 - 10 Feb 2022
Cited by 8 | Viewed by 3581
Abstract
mRNA processing factors are increasingly being recognized as important regulators of genome stability. By preventing and resolving RNA:DNA hybrids that form co-transcriptionally, these proteins help avoid replication–transcription conflicts and thus contribute to genome stability through their normal function in RNA maturation. Some of [...] Read more.
mRNA processing factors are increasingly being recognized as important regulators of genome stability. By preventing and resolving RNA:DNA hybrids that form co-transcriptionally, these proteins help avoid replication–transcription conflicts and thus contribute to genome stability through their normal function in RNA maturation. Some of these factors also have direct roles in the activation of the DNA damage response and in DNA repair. One of the most intriguing cases is that of PRP19, an evolutionarily conserved essential E3 ubiquitin ligase that promotes mRNA splicing, but also participates directly in ATR activation, double-strand break resection and mitosis. Here, we review historical and recent work on PRP19 and its associated proteins, highlighting their multifarious cellular functions as central regulators of spliceosome activity, R-loop homeostasis, DNA damage signaling and repair and cell division. Finally, we discuss open questions that are bound to shed further light on the functions of PRP19-containing complexes in both normal and cancer cells. Full article
(This article belongs to the Special Issue The Role of the Ubiquitin-Proteasome-System in Human Cancer)
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14 pages, 944 KiB  
Review
The Central Role of the Ubiquitin–Proteasome System in EBV-Mediated Oncogenesis
by Yonggang Pei and Erle S. Robertson
Cancers 2022, 14(3), 611; https://doi.org/10.3390/cancers14030611 - 26 Jan 2022
Cited by 9 | Viewed by 3599
Abstract
Deregulation of the ubiquitin–proteasome system (UPS) plays a critical role in the development of numerous human cancers. Epstein–Barr virus (EBV), the first known human tumor virus, has evolved distinct molecular mechanisms to manipulate the ubiquitin–proteasome system, facilitate its successful infection, and drive opportunistic [...] Read more.
Deregulation of the ubiquitin–proteasome system (UPS) plays a critical role in the development of numerous human cancers. Epstein–Barr virus (EBV), the first known human tumor virus, has evolved distinct molecular mechanisms to manipulate the ubiquitin–proteasome system, facilitate its successful infection, and drive opportunistic cancers. The interactions of EBV antigens with the ubiquitin–proteasome system can lead to oncogenesis through the targeting of cellular factors involved in proliferation. Recent studies highlight the central role of the ubiquitin–proteasome system in EBV infection. This review will summarize the versatile strategies in EBV-mediated oncogenesis that contribute to the development of specific therapeutic approaches to treat EBV-associated malignancies. Full article
(This article belongs to the Special Issue The Role of the Ubiquitin-Proteasome-System in Human Cancer)
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32 pages, 1068 KiB  
Review
Therapeutic Potential of Targeting the SUMO Pathway in Cancer
by Antti Kukkula, Veera K. Ojala, Lourdes M. Mendez, Lea Sistonen, Klaus Elenius and Maria Sundvall
Cancers 2021, 13(17), 4402; https://doi.org/10.3390/cancers13174402 - 31 Aug 2021
Cited by 40 | Viewed by 7711
Abstract
SUMOylation is a dynamic and reversible post-translational modification, characterized more than 20 years ago, that regulates protein function at multiple levels. Key oncoproteins and tumor suppressors are SUMO substrates. In addition to alterations in SUMO pathway activity due to conditions typically present in [...] Read more.
SUMOylation is a dynamic and reversible post-translational modification, characterized more than 20 years ago, that regulates protein function at multiple levels. Key oncoproteins and tumor suppressors are SUMO substrates. In addition to alterations in SUMO pathway activity due to conditions typically present in cancer, such as hypoxia, the SUMO machinery components are deregulated at the genomic level in cancer. The delicate balance between SUMOylation and deSUMOylation is regulated by SENP enzymes possessing SUMO-deconjugation activity. Dysregulation of SUMO machinery components can disrupt the balance of SUMOylation, contributing to the tumorigenesis and drug resistance of various cancers in a context-dependent manner. Many molecular mechanisms relevant to the pathogenesis of specific cancers involve SUMO, highlighting the potential relevance of SUMO machinery components as therapeutic targets. Recent advances in the development of inhibitors targeting SUMOylation and deSUMOylation permit evaluation of the therapeutic potential of targeting the SUMO pathway in cancer. Finally, the first drug inhibiting SUMO pathway, TAK-981, is currently also being evaluated in clinical trials in cancer patients. Intriguingly, the inhibition of SUMOylation may also have the potential to activate the anti-tumor immune response. Here, we comprehensively and systematically review the recent developments in understanding the role of SUMOylation in cancer and specifically focus on elaborating the scientific rationale of targeting the SUMO pathway in different cancers. Full article
(This article belongs to the Special Issue The Role of the Ubiquitin-Proteasome-System in Human Cancer)
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20 pages, 3536 KiB  
Review
The Ubiquitin Proteasome System in Genome Stability and Cancer
by Jonathan J. Morgan and Lisa J. Crawford
Cancers 2021, 13(9), 2235; https://doi.org/10.3390/cancers13092235 - 6 May 2021
Cited by 17 | Viewed by 4292
Abstract
Faithful DNA replication during cellular division is essential to maintain genome stability and cells have developed a sophisticated network of regulatory systems to ensure its integrity. Disruption of these control mechanisms can lead to loss of genomic stability, a key hallmark of cancer. [...] Read more.
Faithful DNA replication during cellular division is essential to maintain genome stability and cells have developed a sophisticated network of regulatory systems to ensure its integrity. Disruption of these control mechanisms can lead to loss of genomic stability, a key hallmark of cancer. Ubiquitination is one of the most abundant regulatory post-translational modifications and plays a pivotal role in controlling replication progression, repair of DNA and genome stability. Dysregulation of the ubiquitin proteasome system (UPS) can contribute to the initiation and progression of neoplastic transformation. In this review we provide an overview of the UPS and summarize its involvement in replication and replicative stress, along with DNA damage repair. Finally, we discuss how the UPS presents as an emerging source for novel therapeutic interventions aimed at targeting genomic instability, which could be utilized in the treatment and management of cancer. Full article
(This article belongs to the Special Issue The Role of the Ubiquitin-Proteasome-System in Human Cancer)
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23 pages, 775 KiB  
Review
Dysregulation of the Ubiquitin Proteasome System in Human Malignancies: A Window for Therapeutic Intervention
by Chee Wai Fhu and Azhar Ali
Cancers 2021, 13(7), 1513; https://doi.org/10.3390/cancers13071513 - 25 Mar 2021
Cited by 30 | Viewed by 6092
Abstract
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 [...] Read more.
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. Here, we provide a comprehensive general overview on the regulation and roles of UPS and discuss functional links of dysregulated UPS in human malignancies. Inhibitors developed against components of the UPS, which include U.S. Food and Drug Administration FDA-approved and those currently undergoing clinical trials, are also presented in this review. Full article
(This article belongs to the Special Issue The Role of the Ubiquitin-Proteasome-System in Human Cancer)
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31 pages, 2865 KiB  
Review
Deubiquitinating Enzyme-Mediated Signaling Networks in Cancer Stem Cells
by Kamini Kaushal and Suresh Ramakrishna
Cancers 2020, 12(11), 3253; https://doi.org/10.3390/cancers12113253 - 4 Nov 2020
Cited by 10 | Viewed by 4704
Abstract
Cancer stem cells (CSCs) have both the capacity for self-renewal and the potential to differentiate and contribute to multiple tumor properties, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. Thus, CSCs are considered to be promising therapeutic targets for cancer therapy. [...] Read more.
Cancer stem cells (CSCs) have both the capacity for self-renewal and the potential to differentiate and contribute to multiple tumor properties, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. Thus, CSCs are considered to be promising therapeutic targets for cancer therapy. The function of CSCs can be regulated by ubiquitination and deubiquitination of proteins related to the specific stemness of the cells executing various stem cell fate choices. To regulate the balance between ubiquitination and deubiquitination processes, the disassembly of ubiquitin chains from specific substrates by deubiquitinating enzymes (DUBs) is crucial. Several key developmental and signaling pathways have been shown to play essential roles in this regulation. Growing evidence suggests that overactive or abnormal signaling within and among these pathways may contribute to the survival of CSCs. These signaling pathways have been experimentally shown to mediate various stem cell properties, such as self-renewal, cell fate decisions, survival, proliferation, and differentiation. In this review, we focus on the DUBs involved in CSCs signaling pathways, which are vital in regulating their stem-cell fate determination. Full article
(This article belongs to the Special Issue The Role of the Ubiquitin-Proteasome-System in Human Cancer)
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14 pages, 12302 KiB  
Brief Report
HERC1 Regulates Breast Cancer Cells Migration and Invasion
by Fabiana Alejandra Rossi, Ezequiel Hernán Calvo Roitberg, Juliana Haydeé Enriqué Steinberg, Molishree Umesh Joshi, Joaquín Maximiliano Espinosa and Mario Rossi
Cancers 2021, 13(6), 1309; https://doi.org/10.3390/cancers13061309 - 15 Mar 2021
Cited by 11 | Viewed by 3289
Abstract
Tumor cell migration and invasion into adjacent tissues is one of the hallmarks of cancer and the first step towards secondary tumors formation, which represents the leading cause of cancer-related deaths. This process is considered an unmet clinical need in the treatment of [...] Read more.
Tumor cell migration and invasion into adjacent tissues is one of the hallmarks of cancer and the first step towards secondary tumors formation, which represents the leading cause of cancer-related deaths. This process is considered an unmet clinical need in the treatment of this disease, particularly in breast cancers characterized by high aggressiveness and metastatic potential. To identify and characterize genes with novel functions as regulators of tumor cell migration and invasion, we performed a genetic loss-of-function screen using a shRNA library directed against the Ubiquitin Proteasome System (UPS) in a highly invasive breast cancer derived cell line. Among the candidates, we validated HERC1 as a gene regulating cell migration and invasion. Furthermore, using animal models, our results indicate that HERC1 silencing affects primary tumor growth and lung colonization. Finally, we conducted an in silico analysis using publicly available protein expression data and observed an inverse correlation between HERC1 expression levels and breast cancer patients’ overall survival. Altogether, our findings demonstrate that HERC1 might represent a novel therapeutic target for the development or improvement of breast cancer treatment. Full article
(This article belongs to the Special Issue The Role of the Ubiquitin-Proteasome-System in Human Cancer)
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