Ubiquitination of Nonhistone Proteins in Cancer Development and Treatment

Ubiquitination, a crucial post-translation modification, regulates the localization and stability of the substrate proteins including nonhistone proteins. The ubiquitin-proteasome system (UPS) on nonhistone proteins plays a critical role in many cellular processes such as DNA repair, transcription, signal transduction, and apoptosis. Its dysregulation induces various diseases including cancer, and the identification of this process may provide potential therapeutic targets for cancer treatment. In this review, we summarize the regulatory roles of key UPS members on major nonhistone substrates in cancer-related processes, such as cell cycle, cell proliferation, apoptosis, DNA damage repair, inflammation, and T cell dysfunction in cancer. In addition, we also highlight novel therapeutic interventions targeting the UPS members (E1s, E2s, E3s, proteasomes, and deubiquitinating enzymes). Furthermore, we discuss the application of proteolysis-targeting chimeras (PROTACs) technology as a novel anticancer therapeutic strategy in modulating protein target levels with the aid of UPS.

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USP47-Mediated Deubiquitination and Stabilization of TCEA3 Attenuates Pyroptosis and Apoptosis of Colorectal Cancer Cells Induced by Chemotherapeutic Doxorubicin

Frontiers in Pharmacology ◽

10.3389/fphar.2021.713322 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiaodan Hou ◽

Jun Xia ◽

Yuan Feng ◽

Long Cui ◽

Yili Yang ◽

...

Keyword(s):

Ectopic Expression ◽

Elongation Factor ◽

Disease Free Survival ◽

Ubiquitin Proteasome System ◽

Deubiquitinating Enzyme ◽

Deubiquitinating Enzymes ◽

Cellular Processes ◽

Colorectal Cancer Cells ◽

Ubiquitin Proteasome ◽

Resistance To Doxorubicin

The ubiquitin–proteasome system regulates a variety of cellular processes including growth, differentiation and apoptosis. While E1, E2, and E3 are responsible for the conjugation of ubiquitin to substrates, deubiquitinating enzymes (DUBs) reverse the process to remove ubiquitin and edit ubiquitin chains, which have profound effects on substrates’ degradation, localization, and activities. In the present study, we found that the deubiquitinating enzyme USP47 was markedly decreased in primary colorectal cancers (CRC). Its reduced expression was associated with shorter disease-free survival of CRC patients. In cultured CRC cells, knockdown of USP47 increased pyroptosis and apoptosis induced by chemotherapeutic doxorubicin. We found that USP47 was able to bind with transcription elongation factor a3 (TCEA3) and regulated its deubiquitination and intracellular level. While ectopic expression of USP47 increased cellular TCEA3 and resistance to doxorubicin, the effect was markedly attenuated by TCEA3 knockdown. Further analysis showed that the level of pro-apoptotic Bax was regulated by TCEA3. These results indicated that the USP47-TCEA3 axis modulates cell pyroptosis and apoptosis and may serve as a target for therapeutic intervention in CRC.

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The Ubiquitin Proteasome System in Genome Stability and Cancer

Cancers ◽

10.3390/cancers13092235 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2235

Author(s):

Jonathan J. Morgan ◽

Lisa J. Crawford

Keyword(s):

Genome Stability ◽

Ubiquitin Proteasome System ◽

Therapeutic Interventions ◽

Control Mechanisms ◽

Cellular Division ◽

Post Translational Modifications ◽

Replicative Stress ◽

Regulatory Systems ◽

Damage Repair ◽

Ubiquitin Proteasome

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.

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A Nut for Every Bolt: Subunit-Selective Inhibitors of the Immunoproteasome and Their Therapeutic Potential

Cells ◽

10.3390/cells10081929 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1929

Author(s):

Eva M. Huber ◽

Michael Groll

Keyword(s):

Cell Cycle Progression ◽

Therapeutic Potential ◽

Cell Signalling ◽

Selective Inhibition ◽

Ubiquitin Proteasome System ◽

Cellular Processes ◽

Chemical Structures ◽

Phase Ii Clinical Trials ◽

Ubiquitin Proteasome ◽

Recent Trends

At the heart of the ubiquitin–proteasome system, the 20S proteasome core particle (CP) breaks down the majority of intracellular proteins tagged for destruction. Thereby, the CP controls many cellular processes including cell cycle progression and cell signalling. Inhibitors of the CP can suppress these essential biological pathways, resulting in cytotoxicity, an effect that is beneficial for the treatment of certain blood cancer patients. During the last decade, several preclinical studies demonstrated that selective inhibition of the immunoproteasome (iCP), one of several CP variants in mammals, suppresses autoimmune diseases without inducing toxic side effects. These promising findings led to the identification of natural and synthetic iCP inhibitors with distinct chemical structures, varying potency and subunit selectivity. This review presents the most prominent iCP inhibitors with respect to possible scientific and medicinal applications, and discloses recent trends towards pan-immunoproteasome reactive inhibitors that cumulated in phase II clinical trials of the lead compound KZR-616 for chronic inflammations.

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Accumulation of Mutant Huntingtin Fragments in Aggresome-like Inclusion Bodies as a Result of Insufficient Protein Degradation

Molecular Biology of the Cell ◽

10.1091/mbc.12.5.1393 ◽

2001 ◽

Vol 12 (5) ◽

pp. 1393-1407 ◽

Cited By ~ 423

Author(s):

Stephanie Waelter ◽

Annett Boeddrich ◽

Rudi Lurz ◽

Eberhard Scherzinger ◽

Gerhild Lueder ◽

...

Keyword(s):

Inclusion Bodies ◽

Rna Binding ◽

Ubiquitin Proteasome System ◽

26S Proteasome ◽

Therapeutic Interventions ◽

Ultrastructural Changes ◽

Huntingtin Protein ◽

Fibrillar Morphology ◽

Exon 1 ◽

Ubiquitin Proteasome

The huntingtin exon 1 proteins with a polyglutamine repeat in the pathological range (51 or 83 glutamines), but not with a polyglutamine tract in the normal range (20 glutamines), form aggresome-like perinuclear inclusions in human 293 Tet-Off cells. These structures contain aggregated, ubiquitinated huntingtin exon 1 protein with a characteristic fibrillar morphology. Inclusion bodies with truncated huntingtin protein are formed at centrosomes and are surrounded by vimentin filaments. Inhibition of proteasome activity resulted in a twofold increase in the amount of ubiquitinated, SDS-resistant aggregates, indicating that inclusion bodies accumulate when the capacity of the ubiquitin–proteasome system to degrade aggregation-prone huntingtin protein is exhausted. Immunofluorescence and electron microscopy with immunogold labeling revealed that the 20S, 19S, and 11S subunits of the 26S proteasome, the molecular chaperones BiP/GRP78, Hsp70, and Hsp40, as well as the RNA-binding protein TIA-1, the potential chaperone 14–3-3, and α-synuclein colocalize with the perinuclear inclusions. In 293 Tet-Off cells, inclusion body formation also resulted in cell toxicity and dramatic ultrastructural changes such as indentations and disruption of the nuclear envelope. Concentration of mitochondria around the inclusions and cytoplasmic vacuolation were also observed. Together these findings support the hypothesis that the ATP-dependent ubiquitin–proteasome system is a potential target for therapeutic interventions in glutamine repeat disorders.

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Ubiquitin carboxyl-terminal hydrolases are required for period maintenance of the circadian clock at high temperature in Arabidopsis

Scientific Reports ◽

10.1038/s41598-019-53229-8 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Ryosuke Hayama ◽

Peizhen Yang ◽

Federico Valverde ◽

Tsuyoshi Mizoguchi ◽

Ikuyo Furutani-Hayama ◽

...

Keyword(s):

Circadian Clock ◽

High Temperatures ◽

Elevated Temperatures ◽

Control Period ◽

Ubiquitin Proteasome System ◽

26S Proteasome ◽

Cellular Processes ◽

Control Functions ◽

Ubiquitin Proteasome ◽

Carboxyl Terminal

AbstractProtein ubiquitylation participates in a number of essential cellular processes including signal transduction and transcription, often by initiating the degradation of specific substrates through the 26S proteasome. Within the ubiquitin-proteasome system, deubiquitylating enzymes (DUBs) not only help generate and maintain the supply of free ubiquitin monomers, they also directly control functions and activities of specific target proteins by modulating the pool of ubiquitylated species. Ubiquitin carboxyl-terminal hydrolases (UCHs) belong to an enzymatic subclass of DUBs, and are represented by three members in Arabidopsis, UCH1, UCH2 and UCH3. UCH1 and UCH2 influence auxin-dependent developmental pathways in Arabidopsis through their deubiquitylation activities, whereas biological and enzymatic functions of UCH3 remain unclear. Here, we demonstrate that Arabidopsis UCH3 acts to maintain the period of the circadian clock at high temperatures redundantly with UCH1 and UCH2. Whereas single uch1, uch2 and uch3 mutants have weak circadian phenotypes, the triple uch mutant displays a drastic lengthening of period at high temperatures that is more extreme than the uch1 uch2 double mutant. UCH3 also possesses a broad deubiquitylation activity against a range of substrates that link ubiquitin via peptide and isopeptide linkages. While the protein target(s) of UCH1-3 are not yet known, we propose that these DUBs act on one or more factors that control period length of the circadian clock through removal of their bound ubiquitin moieties, thus ensuring that the clock oscillates with a proper period even at elevated temperatures.

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Advances in Deubiquitinating Enzyme Inhibition and Applications in Cancer Therapeutics

Cancers ◽

10.3390/cancers12061579 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1579 ◽

Cited By ~ 5

Author(s):

Ainsley Mike Antao ◽

Apoorvi Tyagi ◽

Kye-Seong Kim ◽

Suresh Ramakrishna

Keyword(s):

Protein Interactions ◽

Cancer Therapeutics ◽

Ubiquitin Proteasome System ◽

Deubiquitinating Enzyme ◽

Protein Protein Interactions ◽

Deubiquitinating Enzymes ◽

Cellular Functions ◽

E3 Ligases ◽

Ubiquitin Proteasome ◽

Target Cancer

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.

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Ubiquitination and Ubiquitin-Like Modifications in Multiple Myeloma: Biology and Therapy

Cancers ◽

10.3390/cancers12123764 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3764

Author(s):

Matthias Wirth ◽

Markus Schick ◽

Ulrich Keller ◽

Jan Krönke

Keyword(s):

Multiple Myeloma ◽

Translational Regulation ◽

Proteasome Inhibitors ◽

Ubiquitin Proteasome System ◽

Organ Damage ◽

Post Translational Modifications ◽

Damage Repair ◽

Ubiquitin Proteasome ◽

New Treatments ◽

Effective Drugs

Multiple myeloma is a genetically heterogeneous plasma cell malignancy characterized by organ damage and a massive production of (in-)complete monoclonal antibodies. Coping with protein homeostasis and post-translational regulation is therefore essential for multiple myeloma cells to survive. Furthermore, post-translational modifications such as ubiquitination and SUMOylation play key roles in essential pathways in multiple myeloma, including NFκB signaling, epigenetic regulation, as well as DNA damage repair. Drugs modulating the ubiquitin–proteasome system, such as proteasome inhibitors and thalidomide analogs, are approved and highly effective drugs in multiple myeloma. In this review, we focus on ubiquitin and ubiquitin-like modifications in the biology and current developments of new treatments for multiple myeloma.

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Protein Stability of Pyruvate Kinase Isozyme M2 Is Mediated by HAUSP

Cancers ◽

10.3390/cancers12061548 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1548 ◽

Cited By ~ 1

Author(s):

Hae-Seul Choi ◽

Chang-Zhu Pei ◽

Jun-Hyeok Park ◽

Soo-Yeon Kim ◽

Seung-Yeon Song ◽

...

Keyword(s):

Pyruvate Kinase ◽

Tumor Development ◽

Direct Interaction ◽

Ubiquitin Proteasome System ◽

Binding Motif ◽

Deubiquitinating Enzymes ◽

Flight Mass Spectrometry ◽

Specific Protease ◽

Ubiquitin Proteasome ◽

Mutant Forms

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.

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TRIM Proteins and Their Roles in the Influenza Virus Life Cycle

Microorganisms ◽

10.3390/microorganisms8091424 ◽

2020 ◽

Vol 8 (9) ◽

pp. 1424

Author(s):

Hye-Ra Lee ◽

Myoung Kyu Lee ◽

Chan Woo Kim ◽

Meehyein Kim

Keyword(s):

Influenza Virus ◽

Signaling Pathways ◽

Viral Infections ◽

Influenza Virus Infection ◽

Ubiquitin Proteasome System ◽

Viral Propagation ◽

Cellular Processes ◽

Ubiquitin Proteasome ◽

Immune Sensing ◽

Trim Proteins

The ubiquitin-proteasome system (UPS) has been recognized for regulating fundamental cellular processes, followed by induction of proteasomal degradation of target proteins, and triggers multiple signaling pathways that are crucial for numerous aspects of cellular physiology. Especially tripartite motif (TRIM) proteins, well-known E3 ubiquitin ligases, emerge as having critical roles in several antiviral signaling pathways against varying viral infections. Here we highlight recent advances in the study of antiviral roles of TRIM proteins toward influenza virus infection in terms of the modulation of pathogen recognition receptor (PRR)-mediated innate immune sensing, direct obstruction of influenza viral propagation, and participation in virus-induced autophagy.

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The UNC-45 chaperone mediates sarcomere assembly through myosin degradation in Caenorhabditis elegans

The Journal of Cell Biology ◽

10.1083/jcb.200607084 ◽

2007 ◽

Vol 177 (2) ◽

pp. 205-210 ◽

Cited By ~ 61

Author(s):

Megan L. Landsverk ◽

Shumin Li ◽

Alex H. Hutagalung ◽

Ayaz Najafov ◽

Thorsten Hoppe ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Proteasome Inhibition ◽

Thick Filament ◽

Ubiquitin Proteasome System ◽

Loss Of Function ◽

Cellular Processes ◽

Ubiquitin Proteasome ◽

Myosin Motors ◽

And Function ◽

Sarcomere Assembly

Myosin motors are central to diverse cellular processes in eukaryotes. Homologues of the myosin chaperone UNC-45 have been implicated in the assembly and function of myosin-containing structures in organisms from fungi to humans. In muscle, the assembly of sarcomeric myosin is regulated to produce stable, uniform thick filaments. Loss-of-function mutations in Caenorhabditis elegans UNC-45 lead to decreased muscle myosin accumulation and defective thick filament assembly, resulting in paralyzed animals. We report that transgenic worms overexpressing UNC-45 also display defects in myosin assembly, with decreased myosin content and a mild paralysis phenotype. We find that the reduced myosin accumulation is the result of degradation through the ubiquitin/proteasome system. Partial proteasome inhibition is able to restore myosin protein and worm motility to nearly wild-type levels. These findings suggest a mechanism in which UNC-45–related proteins may contribute to the degradation of myosin in conditions such as heart failure and muscle wasting.

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