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Molecular Cancer Oct 2020Metabolic reprogramming, including enhanced biosynthesis of macromolecules, altered energy metabolism, and maintenance of redox homeostasis, is considered a hallmark of... (Review)
Review
Metabolic reprogramming, including enhanced biosynthesis of macromolecules, altered energy metabolism, and maintenance of redox homeostasis, is considered a hallmark of cancer, sustaining cancer cell growth. Multiple signaling pathways, transcription factors and metabolic enzymes participate in the modulation of cancer metabolism and thus, metabolic reprogramming is a highly complex process. Recent studies have observed that ubiquitination and deubiquitination are involved in the regulation of metabolic reprogramming in cancer cells. As one of the most important type of post-translational modifications, ubiquitination is a multistep enzymatic process, involved in diverse cellular biological activities. Dysregulation of ubiquitination and deubiquitination contributes to various disease, including cancer. Here, we discuss the role of ubiquitination and deubiquitination in the regulation of cancer metabolism, which is aimed at highlighting the importance of this post-translational modification in metabolic reprogramming and supporting the development of new therapeutic approaches for cancer treatment.
Topics: Deubiquitinating Enzymes; Histones; Humans; Neoplasms; Protein Processing, Post-Translational; Signal Transduction; Transcription Factors; Ubiquitination
PubMed: 33004065
DOI: 10.1186/s12943-020-01262-x -
International Journal of Biological... 2022Ubiquitination is vital for multiple cellular processes via dynamic modulation of proteins related to cell growth, proliferation, and survival. Of the ubiquitination... (Review)
Review
Ubiquitination is vital for multiple cellular processes via dynamic modulation of proteins related to cell growth, proliferation, and survival. Of the ubiquitination system components, E3 ubiquitin ligases and deubiquitinases have the most prominent roles in modulating tumor metastasis. This review will briefly summarize the observations and underlying mechanisms of multiple E3 ubiquitin ligases and deubiquitinases to regulate tumor metastasis. Further, we will discuss the relationship and importance between ubiquitination components and tumor progression.
Topics: Deubiquitinating Enzymes; Humans; Neoplasms; Ubiquitin; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 35414786
DOI: 10.7150/ijbs.69411 -
Biochimica Et Biophysica Acta. Gene... Dec 2023The ubiquitin proteasomal system (UPS) represents a highly regulated protein degradation pathway essential for maintaining cellular homeostasis. This system plays a... (Review)
Review
The ubiquitin proteasomal system (UPS) represents a highly regulated protein degradation pathway essential for maintaining cellular homeostasis. This system plays a critical role in several cellular processes, which include DNA damage repair, cell cycle checkpoint control, and immune response regulation. Recently, the UPS has emerged as a promising target for cancer therapeutics due to its involvement in oncogenesis and tumor progression. Here we aim to summarize the key aspects of the UPS and its significance in cancer therapeutics. We begin by elucidating the fundamental components of the UPS, highlighting the role of ubiquitin, E1-E3 ligases, and the proteasome in protein degradation. Furthermore, we discuss the intricate process of ubiquitination and proteasomal degradation, emphasizing the specificity and selectivity achieved through various signaling pathways. The dysregulation of the UPS has been implicated in cancer development and progression. Aberrant ubiquitin-mediated degradation of key regulatory proteins, such as tumor suppressors and oncoproteins, can lead to uncontrolled cell proliferation, evasion of apoptosis, and metastasis. We outline the pivotal role of the UPS in modulating crucial oncogenic pathways, including the regulation of cyclins, transcription factors, Replication stress components and DNA damage response. The increasing recognition of the UPS as a target for cancer therapeutics has spurred the development of small molecules, peptides, and proteasome inhibitors with the potential to restore cellular balance and disrupt tumor growth. We provide an overview of current therapeutic strategies aimed at exploiting the UPS, including the use of proteasome inhibitors, deubiquitinating enzyme inhibitors, and novel E3 ligase modulators. We further discuss novel emerging strategies for the development of next-generation drugs that target proteasome inhibitors. Exploiting the UPS for cancer therapeutics offers promising avenues for developing innovative and effective treatment strategies, providing hope for improved patient outcomes in the fight against cancer.
Topics: Humans; Proteasome Inhibitors; Ubiquitination; Ubiquitin-Protein Ligases; Ubiquitin; Proteasome Endopeptidase Complex; Neoplasms
PubMed: 37633647
DOI: 10.1016/j.bbagrm.2023.194979 -
Cell Death and Differentiation Sep 2022MYC as a transcriptional factor plays a crucial role in breast cancer progression. However, the mechanisms underlying MYC deubiquitination in breast cancer are not well...
MYC as a transcriptional factor plays a crucial role in breast cancer progression. However, the mechanisms underlying MYC deubiquitination in breast cancer are not well defined. Here, we report that OTUB1 is responsible for MYC deubiquitination. OTUB1 could directly deubiquitinate MYC at K323 site, which blocks MYC protein degradation. Moreover, OTUB1 mediated MYC protein stability is also confirmed in OTUB1-knockout mice. Stabilized MYC by OTUB1 promotes its transcriptional activity and induces HK2 expression, which leads to enhance aerobic glycolysis. Therefore, OTUB1 promotes breast tumorigenesis in vivo and in vitro via blocking MYC protein degradation. Taken together, our data identify OTUB1 as a new deubiquitination enzyme for MYC protein degradation, which provides a potential target for breast cancer treatment.
Topics: Animals; Cell Line, Tumor; Cell Transformation, Neoplastic; Cysteine Endopeptidases; Deubiquitinating Enzymes; Glycolysis; Mice; Ubiquitination
PubMed: 35296795
DOI: 10.1038/s41418-022-00971-8 -
The EMBO Journal Mar 2019Deubiquitination of NLRP3 has been suggested to contribute to inflammasome activation, but the roles and molecular mechanisms are still unclear. We here demonstrate that...
Deubiquitination of NLRP3 has been suggested to contribute to inflammasome activation, but the roles and molecular mechanisms are still unclear. We here demonstrate that ABRO1, a subunit of the BRISC deubiquitinase complex, is necessary for optimal NLRP3-ASC complex formation, ASC oligomerization, caspase-1 activation, and IL-1β and IL-18 production upon treatment with NLRP3 ligands after the priming step, indicating that efficient NLRP3 activation requires ABRO1. Moreover, we report that ABRO1 deficiency results in a remarkable attenuation in the syndrome severity of NLRP3-associated inflammatory diseases, including MSU- and Alum-induced peritonitis and LPS-induced sepsis in mice. Mechanistic studies reveal that LPS priming induces ABRO1 binding to NLRP3 in an S194 phosphorylation-dependent manner, subsequently recruiting the BRISC to remove K63-linked ubiquitin chains of NLRP3 upon stimulation with activators. Furthermore, deficiency of BRCC3, the catalytically active component of BRISC, displays similar phenotypes to ABRO1 knockout mice. Our findings reveal an ABRO1-mediated regulatory signaling system that controls activation of the NLRP3 inflammasome and provide novel potential targets for treating NLRP3-associated inflammatory diseases.
Topics: Animals; Deubiquitinating Enzymes; Female; Inflammasomes; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NLR Family, Pyrin Domain-Containing 3 Protein; Nuclear Matrix-Associated Proteins; Peritonitis; Phosphorylation; Proteolysis; Reactive Oxygen Species; Signal Transduction; Ubiquitin-Specific Proteases; Ubiquitination; Ubiquitins
PubMed: 30787184
DOI: 10.15252/embj.2018100376 -
International Journal of Molecular... May 2021Oral health is an integral part of the general health and well-being of individuals. The presence of oral disease is potentially indicative of a number of systemic... (Review)
Review
Oral health is an integral part of the general health and well-being of individuals. The presence of oral disease is potentially indicative of a number of systemic diseases and may contribute to their early diagnosis and treatment. The ubiquitin (Ub) system has been shown to play a role in cellular immune response, cellular development, and programmed cell death. Ubiquitination is a post-translational modification that occurs in eukaryotes. Its mechanism involves a number of factors, including Ub-activating enzymes, Ub-conjugating enzymes, and Ub protein ligases. Deubiquitinating enzymes, which are proteases that reversely modify proteins by removing Ub or Ub-like molecules or remodeling Ub chains on target proteins, have recently been regarded as crucial regulators of ubiquitination-mediated degradation and are known to significantly affect cellular pathways, a number of biological processes, DNA damage response, and DNA repair pathways. Research has increasingly shown evidence of the relationship between ubiquitination, deubiquitination, and oral disease. This review investigates recent progress in discoveries in diseased oral sites and discusses the roles of ubiquitination and deubiquitination in oral disease.
Topics: Cracked Tooth Syndrome; Dental Caries; Dentin Sensitivity; Deubiquitinating Enzymes; Forecasting; Gingivitis; Humans; Mouth Diseases; Mouth Neoplasms; Neoplasm Proteins; Periodontal Diseases; Proteasome Endopeptidase Complex; Protein Processing, Post-Translational; Tooth Diseases; Ubiquitin-Activating Enzymes; Ubiquitinated Proteins; Ubiquitination
PubMed: 34070986
DOI: 10.3390/ijms22115488 -
Frontiers in Immunology 2023Immune evasion is essential for carcinogenesis and cancer progression. Programmed death-ligand 1 (PD-L1), a critical immune checkpoint molecule, interacts with... (Review)
Review
Immune evasion is essential for carcinogenesis and cancer progression. Programmed death-ligand 1 (PD-L1), a critical immune checkpoint molecule, interacts with programmed death receptor-1 (PD-1) on immune cells to suppress anti-tumor immune responses. In the past decade, antibodies targeting PD-1/PD-L1 have tremendously altered cancer treatment paradigms. Post-translational modifications have been reported as key regulators of PD-L1 expression. Among these modifications, ubiquitination and deubiquitination are reversible processes that dynamically control protein degradation and stabilization. Deubiquitinating enzymes (DUBs) are responsible for deubiquitination and have emerged as crucial players in tumor growth, progression, and immune evasion. Recently, studies have highlighted the participation of DUBs in deubiquitinating PD-L1 and modulating its expression. Here, we review the recent developments in deubiquitination modifications of PD-L1 and focus on the underlying mechanisms and effects on anti-tumor immunity.
Topics: Humans; B7-H1 Antigen; Programmed Cell Death 1 Receptor; Neoplasms; Immunotherapy
PubMed: 37415977
DOI: 10.3389/fimmu.2023.1228200 -
Acta Pharmaceutica Sinica. B Jul 2023Deubiquitinating enzymes (DUBs) or deubiquitinases facilitate the escape of multiple proteins from ubiquitin‒proteasome degradation and are critical for regulating... (Review)
Review
Deubiquitinating enzymes (DUBs) or deubiquitinases facilitate the escape of multiple proteins from ubiquitin‒proteasome degradation and are critical for regulating protein expression levels . Therefore, dissecting the underlying mechanism of DUB recognition is needed to advance the development of drugs related to DUB signaling pathways. To data, extensive studies on the ubiquitin chain specificity of DUBs have been reported, but substrate protein recognition is still not clearly understood. As a breakthrough, the scaffolding role may be significant to substrate protein selectivity. From this perspective, we systematically characterized the scaffolding proteins and complexes contributing to DUB substrate selectivity. Furthermore, we proposed a deubiquitination complex platform (DCP) as a potentially generic mechanism for DUB substrate recognition based on known examples, which might fill the gaps in the understanding of DUB substrate specificity.
PubMed: 37521861
DOI: 10.1016/j.apsb.2023.02.019 -
Journal of Experimental & Clinical... Nov 2022Radioresistance is the primary cause of nasopharyngeal carcinoma (NPC) treatment failure. Previous studies have focused on the deficits in cellular apoptosis as a...
BACKGROUND
Radioresistance is the primary cause of nasopharyngeal carcinoma (NPC) treatment failure. Previous studies have focused on the deficits in cellular apoptosis as a mechanism for radioresistance; however, additional potential death modes involved in modulating radiosensitivity of NPC have not been explored.
METHODS
Pyroptosis was assessed by phase-contrast imaging, LDH release assays, live cell imaging, and Western blotting. In vitro and in vivo assays were used to investigate the function of gasdermin E (GSDME) and ovarian tumor family deubiquitinase 4 (OTUD4). NPC tissues were analyzed using Western blotting, immunohistochemistry, and real-time PCR. The molecular mechanism was determined using immunoprecipitation assays and mass spectrometry.
RESULTS
Live cell imaging revealed that 40-75% of irradiation-induced dead NPC cells were pyroptotic cells. Furthermore, irradiation-induced pyroptosis is triggered by GSDME, which are cleaved by activated caspase-3 in the intrinsic mitochondrial pathway. Additionally, GSDME was significantly downregulated in radioresistant NPC specimens. Low GSDME expression was a predictor of worse prognosis and conferred NPC radioresistance both in vitro and in vivo. Mechanistically, OTUD4 deubiquitinated and stabilized GSDME, enhancing radiosensitivity of NPC cells by promoting pyroptosis. Clinically, OTUD4 was significantly correlated with GSDME in NPC biopsies, and patients with low expression of both OTUD4 and GSDME suffered the worst radiotherapy response and survival.
CONCLUSIONS
GSDME-dependent pyroptosis is a critical determinant of radiosensitivity in NPC, and is modulated by OTUD4 via deubiquitinating and stabilizing GSDME. These findings reveal a promising novel direction to investigate radioresistance and suggest potential therapeutic targets for sensitizing NPC to radiotherapy.
Topics: Female; Humans; Nasopharyngeal Carcinoma; Pyroptosis; Cell Line, Tumor; Radiation Tolerance; Ovarian Neoplasms; Nasopharyngeal Neoplasms; Ubiquitin-Specific Proteases
PubMed: 36411454
DOI: 10.1186/s13046-022-02533-9 -
Oncology Reports Mar 2019The Hippo signaling pathway is considered to be a tissue growth regulator and tumor suppressor pathway that controls cell proliferation, differentiation, survival,... (Review)
Review
The Hippo signaling pathway is considered to be a tissue growth regulator and tumor suppressor pathway that controls cell proliferation, differentiation, survival, regeneration and tissue homeostasis. Defects in Hippo kinases and hyperactivation of transcriptional co‑activator with PDZ‑binding motif and Yes‑associated protein (YAP) may contribute to the development of different types of cancer. The Hippo pathway is regulated in a variety of way, of which ubiquitination is of considerable importance. Ubiquitination is a crucial post‑translational protein modification in cancer cells and is an applicable target for pharmacological intervention. Ubiquitin modifications are involved in regulating various physiological processes and are counteracted by deubiquitination. Imbalanced ubiquitination‑deubiquitination is closely associated with tumor initiation and progression. Therefore, the examination of the specific association between the Hippo pathway and ubiquitination is of interest. The present study reviews the modulatory mechanism of ubiquitination‑deubiquitination in the Hippo signaling pathway, the recent progress in identifying therapeutic targets and strategies, and the future directions in the field that may contribute to better tumor diagnosis and treatment.
Topics: Adaptor Proteins, Signal Transducing; Antineoplastic Agents; Biomarkers, Tumor; Carcinogenesis; Deubiquitinating Enzymes; Disease Progression; Hippo Signaling Pathway; Humans; Neoplasms; Phosphoproteins; Protein Serine-Threonine Kinases; Signal Transduction; Transcription Factors; Ubiquitin; Ubiquitin-Protein Ligase Complexes; Ubiquitination; YAP-Signaling Proteins
PubMed: 30628704
DOI: 10.3892/or.2019.6956