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Targeting the Ubiquitin Pathway in Cancer

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

Deadline for manuscript submissions: closed (30 June 2020) | Viewed by 69778

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Prof. Dr. Yasusei Kudo

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Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto, Tokushima 770-8504, Japan
Interests: head and neck cancer; cell cycle; ubiquitin-proteasome pathway; invasion; metastasis; oral pathology

Special Issue Information

Dear Colleagues,

The ubiquitin–proteasome system (UPS) is a common mechanism by which cells renew their intracellular proteins and maintain protein homeostasis. Recently, abnormal regulation of UPS has been found to be involved in various diseases, including cancer. A series of enzymes known as E1s (ubiquitin-activating enzymes), E2s (ubiquitin-conjugating enzymes), various E3s (ubiquitin ligases), and deubiquitinating (DUB) enzymes in the UPS could serve as potential drug targets in cancers. In addition, chimeric small molecules which are designed to induce degradation of their target proteins via the UPS can be used for cancer therapy. In this Special Issue, we focus on abnormalities of the ubiquitin–proteasome system and their potential of therapeutic target in cancer.

Dr. Yasusei Kudo
Guest Editor

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Keywords

Ubiquitin-proteasome pathway
Cancer
Anti-cancer drug

Published Papers (14 papers)

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Research

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15 pages, 2928 KiB

Open AccessArticle

Protein Stability of Pyruvate Kinase Isozyme M2 Is Mediated by HAUSP

by Hae-Seul Choi, Chang-Zhu Pei, Jun-Hyeok Park, Soo-Yeon Kim, Seung-Yeon Song, Gyeong-Jin Shin and Kwang-Hyun Baek

Cancers 2020, 12(6), 1548; https://doi.org/10.3390/cancers12061548 - 12 Jun 2020

Cited by 14 | Viewed by 2912

Abstract

The ubiquitin–proteasome system (UPS) is responsible for proteasomal degradation, regulating the half-life of the protein. Deubiquitinating enzymes (DUBs) are components of the UPS and inhibit degradation by removing ubiquitins from protein substrates. Herpesvirus-associated ubiquitin-specific protease (HAUSP) is one such deubiquitinating enzyme and has been closely associated with tumor development. In a previous study, we isolated putative HAUSP binding substrates by two-dimensional electrophoresis (2-DE) and identified them by matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF/MS) analysis. The analysis showed that pyruvate kinase isoenzyme M2 (PKM2) was likely to be one of the substrates for HAUSP. Further study revealed that PKM2 binds to HAUSP, confirming the interaction between these proteins, and that PKM2 possesses the putative HAUSP binding motif, E or P/AXXS. Therefore, we generated mutant forms of PKM2 S57A, S97A, and S346A, and found that S57A had less binding affinity. In a previous study, we demonstrated that PKM2 is regulated by the UPS, and that HAUSP- as a DUB-acted on PKM2, thus siRNA for HAUSP increases PKM2 ubiquitination. Our present study newly highlights the direct interaction between HAUSP and PKM2. Full article

(This article belongs to the Special Issue Targeting the Ubiquitin Pathway in Cancer)

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18 pages, 2885 KiB

Open AccessArticle

Ubiquitin-Specific Protease 21 Promotes Colorectal Cancer Metastasis by Acting as a Fra-1 Deubiquitinase

by Sun-Il Yun, Hye Kyung Hong, So-Young Yeo, Seok-Hyung Kim, Yong Beom Cho and Kyeong Kyu Kim

Cancers 2020, 12(1), 207; https://doi.org/10.3390/cancers12010207 - 14 Jan 2020

Cited by 27 | Viewed by 4168

Abstract

Fos-related-antigen-1 (Fra-1), a member of the activator protein-1 (AP-1) transcription factor superfamily, has an essential role in cancer progress and metastasis and Fra-1 is considered a therapeutic target in metastatic cancer including metastatic colorectal cancer (mCRC). However, its regulation at protein level has not yet been clearly elucidated. We found that ubiquitin-specific protease 21 (USP21) increases Fra-1 stability by deubiquitinating Fra-1 and enhances the expression of Fra-1 target genes in colon cancer cells. We also showed that USP21 controlled Fra-1-dependent migration and invasion activities. The oncogenic property of USP21 was confirmed by a significant reduction in liver metastasis when USP21-knockdown cancer cells were injected intrasplenically into mice. Consistently, clinicopathological analysis of colorectal cancer patients revealed a correlation of USP21 expression with high-grade carcinoma and life span. These results demonstrate that USP21 enhances Fra-1 stability and AP-1 target gene expression by deubiquitinating Fra-1. Therefore, USP21 is considered an attractive therapeutic target in mCRC with high Fra-1 expression. Full article

(This article belongs to the Special Issue Targeting the Ubiquitin Pathway in Cancer)

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19 pages, 4417 KiB

Open AccessArticle

Epigenetic Silencing of Ubiquitin Specific Protease 4 by Snail1 Contributes to Macrophage-Dependent Inflammation and Therapeutic Resistance in Lung Cancer

by Chao-Yang Lai, Da-Wei Yeh, Chih-Hao Lu, Yi-Ling Liu, Yu-Chen Chuang, Jhen-Wei Ruan, Cheng-Yuan Kao, Li-Rung Huang and Tsung-Hsien Chuang

Cancers 2020, 12(1), 148; https://doi.org/10.3390/cancers12010148 - 8 Jan 2020

Cited by 14 | Viewed by 3471

Abstract

There is a positive feedback loop driving tumorigenesis and tumor growth through coordinated regulation of epigenetics, inflammation, and stemness. Nevertheless, the molecular mechanism linking these processes is not well understood. In this study, we analyzed the correlation of de-ubiquitinases (DUBs) expression with survival data from the OncoLnc database. Among the DUBs analyzed, ubiquitin specific protease 4 (USP4) had the lowest negative Cox coefficient. Low expression of USP4 was associated with poor survival among lung cancer patients and was inversely correlated with expression of stemness and inflammation markers. Expression of USP4 were reduced at more advanced stages of lung cancer. Mechanistically, expression of USP4 was downregulated in snail1-overexpressing and stemness-enriched lung cancer cells. Snail1 was induced in lung cancer cells by interaction with macrophages, and epigenetically suppressed USP4 expression by promoter methylation. Stable knockdown of USP4 in lung cancer cells enhanced inflammatory responses, stemness properties, chemotherapy resistance, and the expression of molecules allowing escape from immunosurveillance. Further, mice injected with USP4 knockdown lung cancer cells demonstrated enhanced tumorigenesis and tumor growth. These results reveal that the Snail1-mediated suppression of USP4 is a potential mechanism to orchestrate epigenetic regulation, inflammation and stemness for macrophage-promoted tumor progression. Full article

(This article belongs to the Special Issue Targeting the Ubiquitin Pathway in Cancer)

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Review

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24 pages, 7434 KiB

Open AccessReview

Histone Monoubiquitination in Chromatin Remodelling: Focus on the Histone H2B Interactome and Cancer

by Deborah J. Marsh, Yue Ma and Kristie-Ann Dickson

Cancers 2020, 12(11), 3462; https://doi.org/10.3390/cancers12113462 - 20 Nov 2020

Cited by 24 | Viewed by 4902

Abstract

Chromatin remodelling is a major mechanism by which cells control fundamental processes including gene expression, the DNA damage response (DDR) and ensuring the genomic plasticity required by stem cells to enable differentiation. The post-translational modification of histone H2B resulting in addition of a single ubiquitin, in humans at lysine 120 (K120; H2Bub1) and in yeast at K123, has key roles in transcriptional elongation associated with the RNA polymerase II-associated factor 1 complex (PAF1C) and in the DDR. H2Bub1 itself has been described as having tumour suppressive roles and a number of cancer-related proteins and/or complexes are recognised as part of the H2Bub1 interactome. These include the RING finger E3 ubiquitin ligases RNF20, RNF40 and BRCA1, the guardian of the genome p53, the PAF1C member CDC73, subunits of the switch/sucrose non-fermenting (SWI/SNF) chromatin remodelling complex and histone methyltransferase complexes DOT1L and COMPASS, as well as multiple deubiquitinases including USP22 and USP44. While globally depleted in many primary human malignancies, including breast, lung and colorectal cancer, H2Bub1 is selectively enriched at the coding region of certain highly expressed genes, including at p53 target genes in response to DNA damage, functioning to exercise transcriptional control of these loci. This review draws together extensive literature to cement a significant role for H2Bub1 in a range of human malignancies and discusses the interplay between key cancer-related proteins and H2Bub1-associated chromatin remodelling. Full article

(This article belongs to the Special Issue Targeting the Ubiquitin Pathway in Cancer)

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19 pages, 1776 KiB

Open AccessReview

The HECT E3 Ligase E6AP/UBE3A as a Therapeutic Target in Cancer and Neurological Disorders

by Asia Owais, Rama K. Mishra and Hiroaki Kiyokawa

Cancers 2020, 12(8), 2108; https://doi.org/10.3390/cancers12082108 - 29 Jul 2020

Cited by 20 | Viewed by 5924

Abstract

The HECT (Homologous to the E6-AP Carboxyl Terminus)-family protein E6AP (E6-associated protein), encoded by the UBE3A gene, is a multifaceted ubiquitin ligase that controls diverse signaling pathways involved in cancer and neurological disorders. The oncogenic role of E6AP in papillomavirus-induced cancers is well known, with its action to trigger p53 degradation in complex with the E6 viral oncoprotein. However, the roles of E6AP in non-viral cancers remain poorly defined. It is well established that loss-of-function alterations of the UBE3A gene cause Angelman syndrome, a severe neurodevelopmental disorder with autosomal dominant inheritance modified by genomic imprinting on chromosome 15q. Moreover, excess dosage of the UBE3A gene markedly increases the penetrance of autism spectrum disorders, suggesting that the expression level of UBE3A must be regulated tightly within a physiologically tolerated range during brain development. In this review, current the knowledge about the substrates of E6AP-mediated ubiquitination and their functions in cancer and neurological disorders is discussed, alongside with the ongoing efforts to pharmacologically modulate this ubiquitin ligase as a promising therapeutic target. Full article

(This article belongs to the Special Issue Targeting the Ubiquitin Pathway in Cancer)

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22 pages, 918 KiB

Open AccessReview

The Ubiquitin Proteasome System in Hematological Malignancies: New Insight into Its Functional Role and Therapeutic Options

by Antonella Di Costanzo, Nunzio Del Gaudio, Lidio Conte and Lucia Altucci

Cancers 2020, 12(7), 1898; https://doi.org/10.3390/cancers12071898 - 14 Jul 2020

Cited by 9 | Viewed by 3400

Abstract

The ubiquitin proteasome system (UPS) is the main cellular degradation machinery designed for controlling turnover of critical proteins involved in cancer pathogenesis, including hematological malignancies. UPS plays a functional role in regulating turnover of key proteins involved in cell cycle arrest, apoptosis and terminal differentiation. When deregulated, it leads to several disorders, including cancer. Several studies indicate that, in some subtypes of human hematological neoplasms such as multiple myeloma and Burkitt’s lymphoma, abnormalities in the UPS made it an attractive therapeutic target due to pro-cancer activity. In this review, we discuss the aberrant role of UPS evaluating its impact in hematological malignancies. Finally, we also review the most promising therapeutic approaches to target UPS as powerful strategies to improve treatment of blood cancers. Full article

(This article belongs to the Special Issue Targeting the Ubiquitin Pathway in Cancer)

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13 pages, 1890 KiB

Open AccessReview

HERC Ubiquitin Ligases in Cancer

by Joan Sala-Gaston, Arturo Martinez-Martinez, Leonardo Pedrazza, L. Francisco Lorenzo-Martín, Rubén Caloto, Xosé R. Bustelo, Francesc Ventura and Jose Luis Rosa

Cancers 2020, 12(6), 1653; https://doi.org/10.3390/cancers12061653 - 22 Jun 2020

Cited by 23 | Viewed by 4742

Abstract

HERC proteins are ubiquitin E3 ligases of the HECT family. The HERC subfamily is composed of six members classified by size into large (HERC1 and HERC2) and small (HERC3–HERC6). HERC family ubiquitin ligases regulate important cellular processes, such as neurodevelopment, DNA damage response, cell proliferation, cell migration, and immune responses. Accumulating evidence also shows that this family plays critical roles in cancer. In this review, we provide an integrated view of the role of these ligases in cancer, highlighting their bivalent functions as either oncogenes or tumor suppressors, depending on the tumor type. We include a discussion of both the molecular mechanisms involved and the potential therapeutic strategies. Full article

(This article belongs to the Special Issue Targeting the Ubiquitin Pathway in Cancer)

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16 pages, 2181 KiB

Open AccessReview

Ubiquitylation-Mediated Fine-Tuning of DNA Double-Strand Break Repair

by Barbara N. Borsos, Hajnalka Majoros and Tibor Pankotai

Cancers 2020, 12(6), 1617; https://doi.org/10.3390/cancers12061617 - 18 Jun 2020

Cited by 10 | Viewed by 4086

Abstract

The proper function of DNA repair is indispensable for eukaryotic cells since accumulation of DNA damages leads to genome instability and is a major cause of oncogenesis. Ubiquitylation and deubiquitylation play a pivotal role in the precise regulation of DNA repair pathways by coordinating the recruitment and removal of repair proteins at the damaged site. Here, we summarize the most important post-translational modifications (PTMs) involved in DNA double-strand break repair. Although we highlight the most relevant PTMs, we focus principally on ubiquitylation-related processes since these are the most robust regulatory pathways among those of DNA repair. Full article

(This article belongs to the Special Issue Targeting the Ubiquitin Pathway in Cancer)

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24 pages, 1701 KiB

Open AccessReview

The Impact of the Ubiquitin System in the Pathogenesis of Squamous Cell Carcinomas

by Veronica Gatti, Francesca Bernassola, Claudio Talora, Gerry Melino and Angelo Peschiaroli

Cancers 2020, 12(6), 1595; https://doi.org/10.3390/cancers12061595 - 16 Jun 2020

Cited by 12 | Viewed by 3260

Abstract

The ubiquitin system is a dynamic regulatory pathway controlling the activity, subcellular localization and stability of a myriad of cellular proteins, which in turn affects cellular homeostasis through the regulation of a variety of signaling cascades. Aberrant activity of key components of the ubiquitin system has been functionally linked with numerous human diseases including the initiation and progression of human tumors. In this review, we will contextualize the importance of the two main components of the ubiquitin system, the E3 ubiquitin ligases (E3s) and deubiquitinating enzymes (DUBs), in the etiology of squamous cell carcinomas (SCCs). We will discuss the signaling pathways regulated by these enzymes, emphasizing the genetic and molecular determinants underlying their deregulation in SCCs. Full article

(This article belongs to the Special Issue Targeting the Ubiquitin Pathway in Cancer)

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36 pages, 1439 KiB

Open AccessReview

Advances in Deubiquitinating Enzyme Inhibition and Applications in Cancer Therapeutics

by Ainsley Mike Antao, Apoorvi Tyagi, Kye-Seong Kim and Suresh Ramakrishna

Cancers 2020, 12(6), 1579; https://doi.org/10.3390/cancers12061579 - 15 Jun 2020

Cited by 75 | Viewed by 7823

Abstract

Since the discovery of the ubiquitin proteasome system (UPS), the roles of ubiquitinating and deubiquitinating enzymes (DUBs) have been widely elucidated. The ubiquitination of proteins regulates many aspects of cellular functions such as protein degradation and localization, and also modifies protein-protein interactions. DUBs cleave the attached ubiquitin moieties from substrates and thereby reverse the process of ubiquitination. The dysregulation of these two paramount pathways has been implicated in numerous diseases, including cancer. Attempts are being made to identify inhibitors of ubiquitin E3 ligases and DUBs that potentially have clinical implications in cancer, making them an important target in the pharmaceutical industry. Therefore, studies in medicine are currently focused on the pharmacological disruption of DUB activity as a rationale to specifically target cancer-causing protein aberrations. Here, we briefly discuss the pathophysiological and physiological roles of DUBs in key cancer-related pathways. We also discuss the clinical applications of promising DUB inhibitors that may contribute to the development of DUBs as key therapeutic targets in the future. Full article

(This article belongs to the Special Issue Targeting the Ubiquitin Pathway in Cancer)

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29 pages, 8494 KiB

Open AccessReview

DUBs Activating the Hedgehog Signaling Pathway: A Promising Therapeutic Target in Cancer

by Francesca Bufalieri, Ludovica Lospinoso Severini, Miriam Caimano, Paola Infante and Lucia Di Marcotullio

Cancers 2020, 12(6), 1518; https://doi.org/10.3390/cancers12061518 - 10 Jun 2020

Cited by 14 | Viewed by 3252

Abstract

The Hedgehog (HH) pathway governs cell proliferation and patterning during embryonic development and is involved in regeneration, homeostasis and stem cell maintenance in adult tissues. The activity of this signaling is finely modulated at multiple levels and its dysregulation contributes to the onset of several human cancers. Ubiquitylation is a coordinated post-translational modification that controls a wide range of cellular functions and signaling transduction pathways. It is mediated by a sequential enzymatic network, in which ubiquitin ligases (E3) and deubiquitylase (DUBs) proteins are the main actors. The dynamic balance of the activity of these enzymes dictates the abundance and the fate of cellular proteins, thus affecting both physiological and pathological processes. Several E3 ligases regulating the stability and activity of the key components of the HH pathway have been identified. Further, DUBs have emerged as novel players in HH signaling transduction, resulting as attractive and promising drug targets. Here, we review the HH-associated DUBs, discussing the consequences of deubiquitylation on the maintenance of the HH pathway activity and its implication in tumorigenesis. We also report the recent progress in the development of selective inhibitors for the DUBs here reviewed, with potential applications for the treatment of HH-related tumors. Full article

(This article belongs to the Special Issue Targeting the Ubiquitin Pathway in Cancer)

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28 pages, 1989 KiB

Open AccessReview

F-Box Proteins and Cancer

by Kanae Yumimoto, Yuhei Yamauchi and Keiichi I. Nakayama

Cancers 2020, 12(5), 1249; https://doi.org/10.3390/cancers12051249 - 15 May 2020

Cited by 30 | Viewed by 5693

Abstract

Controlled protein degradation is essential for the operation of a variety of cellular processes including cell division, growth, and differentiation. Identification of the relations between ubiquitin ligases and their substrates is key to understanding the molecular basis of cancer development and to the discovery of novel targets for cancer therapeutics. F-box proteins function as the substrate recognition subunits of S-phase kinase-associated protein 1 (SKP1)−Cullin1 (CUL1)−F-box protein (SCF) ubiquitin ligase complexes. Here, we summarize the roles of specific F-box proteins that have been shown to function as tumor promoters or suppressors. We also highlight proto-oncoproteins that are targeted for ubiquitylation by multiple F-box proteins, and discuss how these F-box proteins are deployed to regulate their cognate substrates in various situations. Full article

(This article belongs to the Special Issue Targeting the Ubiquitin Pathway in Cancer)

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34 pages, 1670 KiB

Open AccessReview

Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

by Xiaonan Zhang, Stig Linder and Martina Bazzaro

Cancers 2020, 12(4), 902; https://doi.org/10.3390/cancers12040902 - 7 Apr 2020

Cited by 73 | Viewed by 8372

Abstract

Cancer cells are characterized by a higher rate of protein turnover and greater demand for protein homeostasis compared to normal cells. In this scenario, the ubiquitin–proteasome system (UPS), which is responsible for the degradation of over 80% of cellular proteins within mammalian cells, becomes vital to cancer cells, making the UPS a critical target for the discovery of novel cancer therapeutics. This review systematically categorizes all current reported small molecule inhibitors of the various essential components of the UPS, including ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s), the 20S proteasome catalytic core particle (20S CP) and the 19S proteasome regulatory particles (19S RP), as well as their mechanism/s of action and limitations. We also discuss the immunoproteasome which is considered as a prospective therapeutic target of the next generation of proteasome inhibitors in cancer therapies. Full article

(This article belongs to the Special Issue Targeting the Ubiquitin Pathway in Cancer)

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14 pages, 973 KiB

Open AccessReview

Cellular Functions of OCT-3/4 Regulated by Ubiquitination in Proliferating Cells

by Kwang-Hyun Baek, Jihye Choi and Chang-Zhu Pei

Cancers 2020, 12(3), 663; https://doi.org/10.3390/cancers12030663 - 12 Mar 2020

Cited by 16 | Viewed by 6859

Abstract

Octamer-binding transcription factor 3/4 (OCT-3/4), which is involved in the tumorigenesis of somatic cancers, has diverse functions during cancer development. Overexpression of OCT-3/4 has been detected in various human somatic tumors, indicating that OCT-3/4 activation may contribute to the development and progression of cancers. Stem cells can undergo self-renewal, pluripotency, and reprogramming with the help of at least four transcription factors, OCT-3/4, SRY box-containing gene 2 (SOX2), Krüppel-like factor 4 (KLF4), and c-MYC. Of these, OCT-3/4 plays a critical role in maintenance of undifferentiated state of embryonic stem cells (ESCs) and in production of induced pluripotent stem cells (iPSCs). Stem cells can undergo partitioning through mitosis and separate into specific cell types, three embryonic germ layers: the endoderm, the mesoderm, and the trophectoderm. It has been demonstrated that the stability of OCT-3/4 is mediated by the ubiquitin-proteasome system (UPS), which is one of the key cellular mechanisms for cellular homeostasis. The framework of the mechanism is simple, but the proteolytic machinery is complicated. Ubiquitination promotes protein degradation, and ubiquitination of OCT-3/4 leads to regulation of cellular proliferation and differentiation. Therefore, it is expected that OCT-3/4 may play a key role in proliferation and differentiation of proliferating cells. Full article

(This article belongs to the Special Issue Targeting the Ubiquitin Pathway in Cancer)

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