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Oncotarget 2015Carcinogenesis is a complex process tightly regulated at multiple levels by post-translational modifications. Epigenetics plays a major role in cancer development, all... (Review)
Review
Carcinogenesis is a complex process tightly regulated at multiple levels by post-translational modifications. Epigenetics plays a major role in cancer development, all stable changes to the gene expression process that are not a result of a direct change in the DNA code are described as epigenetics. Epigenetic processes are regulated by post-translational modifications including ubiquitination which can directly affect either histones or transcription factors or may target their co-factors and interacting partners exerting an indirect effect. Deubiquitination of these target proteins is equally important and alterations in this pathway can also lead to cancer development, progression and metastasis. Only the correct, unaltered balance between ubiquitination and deubiquitination ensures healthy cellular homeostasis. In this review we focus on the role of deubiquitinating (DUB) enzymes in various aspects of epigenetics including the regulation of transcription factors, histone modifications, DNA damage repair pathways and cell cycle regulation. We discuss the impact of those processes on tumourigenesis and potential therapeutic applications of DUBs for cancer treatment.
Topics: Animals; Cell Cycle; Chromatin; DNA; DNA Damage; DNA Repair; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Histones; Humans; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms; Nuclear Proteins; Protein Binding; Protein Processing, Post-Translational; Transcription Factors; Ubiquitin Thiolesterase; Ubiquitin-Specific Peptidase 7; Ubiquitin-Specific Proteases; Ubiquitination
PubMed: 25962961
DOI: 10.18632/oncotarget.3922 -
Stem Cells International 2016Ubiquitination of core stem cell transcription factors can directly affect stem cell maintenance and differentiation. Ubiquitination and deubiquitination must occur in a... (Review)
Review
Ubiquitination of core stem cell transcription factors can directly affect stem cell maintenance and differentiation. Ubiquitination and deubiquitination must occur in a timely and well-coordinated manner to regulate the protein turnover of several stemness related proteins, resulting in optimal embryonic stem cell maintenance and differentiation. There are two switches: an E3 ubiquitin ligase enzyme that tags ubiquitin molecules to the target proteins for proteolysis and a second enzyme, the deubiquitinating enzyme (DUBs), that performs the opposite action, thereby preventing proteolysis. In order to maintain stemness and to allow for efficient differentiation, both ubiquitination and deubiquitination molecular switches must operate properly in a balanced manner. In this review, we have summarized the importance of the ubiquitination of core stem cell transcription factors, such as Oct3/4, c-Myc, Sox2, Klf4, Nanog, and LIN28, during cellular reprogramming. Furthermore, we emphasize the role of DUBs in regulating core stem cell transcriptional factors and their function in stem cell maintenance and differentiation. We also discuss the possibility of using DUBs, along with core transcription factors, to efficiently generate induced pluripotent stem cells. Our review provides a relatively new understanding regarding the importance of ubiquitination/deubiquitination of stem cell transcription factors for efficient cellular reprogramming.
PubMed: 26880980
DOI: 10.1155/2016/6705927 -
Frontiers in Cell and Developmental... 2021Polycystic ovarian syndrome (PCOS) is an endocrine-related disease related to abnormal folliculogenesis and is a leading cause of infertility worldwide. Inhibition of...
Polycystic ovarian syndrome (PCOS) is an endocrine-related disease related to abnormal folliculogenesis and is a leading cause of infertility worldwide. Inhibition of granulosa cells (GCs) proliferation and increased GCs apoptosis have been identified as the major factors in aberrant follicle maturation. USP25 and PTEN expression in GCs from women with and without PCOS was analyzed using Western blotting. A PCOS-like mouse model was constructed using USP25 knockout and wild-type mice to explore the role of USP25 in PCOS. The human granular cell line KGN was cultured for proliferation and apoptosis assays, and the effect of USP25 on PTEN was investigated after transfection with shRNA-USP25 lentivirus. USP25 expression was found to be elevated in patients and mice with PCOS. With mouse model, we observed a reduction in PCOS symptoms in mice after USP25 deletion. Increased proliferation, reduced apoptosis, activation of the phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway and decreased PTEN expression were found in KGN cells after USP25 knockdown. Finally, we verified that USP25 could deubiquitinate PTEN in KGN cells. In this study, we investigated that USP25 can regulate the PI3K/AKT signaling pathway by deubiquitinating PTEN, thus affecting the proliferation and apoptosis of GCs and contributing to the pathogenesis of PCOS.
PubMed: 34805185
DOI: 10.3389/fcell.2021.779718 -
Frontiers in Physiology 2022Protein ubiquitination with general existence in virtually all eukaryotic cells serves as a significant post-translational modification of cellular proteins, which leads... (Review)
Review
Protein ubiquitination with general existence in virtually all eukaryotic cells serves as a significant post-translational modification of cellular proteins, which leads to the degradation of proteins via the ubiquitin-proteasome system. Deubiquitinating enzymes (DUBs) can reverse the ubiquitination effect by removing the ubiquitin chain from the target protein. Together, these two processes participate in regulating protein stability, function, and localization, thus modulating cell cycle, DNA repair, autophagy, and transcription regulation. Accumulating evidence indicates that the ubiquitination/deubiquitination system regulates reproductive processes, including the cell cycle, oocyte maturation, oocyte-sperm binding, and early embryonic development, primarily by regulating protein stability. This review summarizes the extensive research concerning the role of ubiquitin and DUBs in gametogenesis and early embryonic development, which helps us to understand human pregnancy further.
PubMed: 35910557
DOI: 10.3389/fphys.2022.886261 -
International Journal of Molecular... May 2020The Wnt signaling pathway plays important roles in embryonic development, homeostatic processes, cell differentiation, cell polarity, cell proliferation, and cell... (Review)
Review
The Wnt signaling pathway plays important roles in embryonic development, homeostatic processes, cell differentiation, cell polarity, cell proliferation, and cell migration via the β-catenin binding of Wnt target genes. Dysregulation of Wnt signaling is associated with various diseases such as cancer, aging, Alzheimer's disease, metabolic disease, and pigmentation disorders. Numerous studies entailing the Wnt signaling pathway have been conducted for various cancers. Diverse signaling factors mediate the up- or down-regulation of Wnt signaling through post-translational modifications (PTMs), and aberrant regulation is associated with several different malignancies in humans. Of the numerous PTMs involved, most Wnt signaling factors are regulated by ubiquitination and deubiquitination. Ubiquitination by E3 ligase attaches ubiquitins to target proteins and usually induces proteasomal degradation of Wnt signaling factors such as β-catenin, Axin, GSK3, and Dvl. Conversely, deubiquitination induced by the deubiquitinating enzymes (DUBs) detaches the ubiquitins and modulates the stability of signaling factors. In this review, we discuss the effects of ubiquitination and deubiquitination on the Wnt signaling pathway, and the inhibitors of DUBs that can be applied for cancer therapeutic strategies.
Topics: Animals; Gene Expression Regulation, Neoplastic; Glycogen Synthase Kinase 3; Humans; Mutation; Neoplasms; Protein Binding; Protein Folding; Protein Processing, Post-Translational; Ubiquitin; Ubiquitination; Wnt Signaling Pathway
PubMed: 32486158
DOI: 10.3390/ijms21113904 -
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 -
Cell Reports Apr 2023The rixosome and PRC1 silencing complexes are associated with deSUMOylating and deubiquitinating enzymes, SENP3 and USP7, respectively. How deSUMOylation and...
The rixosome and PRC1 silencing complexes are associated with deSUMOylating and deubiquitinating enzymes, SENP3 and USP7, respectively. How deSUMOylation and deubiquitylation contribute to rixosome- and Polycomb-mediated silencing is not fully understood. Here, we show that the enzymatic activities of SENP3 and USP7 are required for silencing of Polycomb target genes. SENP3 deSUMOylates several rixosome subunits, and this activity is required for association of the rixosome with PRC1. USP7 associates with canonical PRC1 (cPRC1) and deubiquitinates the chromodomain subunits CBX2 and CBX4, and inhibition of USP activity results in disassembly of cPRC1. Finally, both SENP3 and USP7 are required for Polycomb- and rixosome-dependent silencing at an ectopic reporter locus. These findings demonstrate that SUMOylation and ubiquitination regulate the assembly and activities of the rixosome and Polycomb complexes and raise the possibility that these modifications provide regulatory mechanisms that may be utilized during development or in response to environmental challenges.
Topics: Ubiquitin-Specific Peptidase 7; Polycomb Repressive Complex 1; Polycomb-Group Proteins; Ubiquitination; Cell Nucleus
PubMed: 37014752
DOI: 10.1016/j.celrep.2023.112339 -
Frontiers in Immunology 2023Osteoarthritis is non-inflammatory degenerative joint arthritis, which exacerbates disability in elder persons. The molecular mechanisms of osteoarthritis are elusive.... (Review)
Review
Osteoarthritis is non-inflammatory degenerative joint arthritis, which exacerbates disability in elder persons. The molecular mechanisms of osteoarthritis are elusive. Ubiquitination, one type of post-translational modifications, has been demonstrated to accelerate or ameliorate the development and progression of osteoarthritis targeting specific proteins for ubiquitination and determining protein stability and localization. Ubiquitination process can be reversed by a class of deubiquitinases deubiquitination. In this review, we summarize the current knowledge regarding the multifaceted role of E3 ubiquitin ligases in the pathogenesis of osteoarthritis. We also describe the molecular insight of deubiquitinases into osteoarthritis processes. Moreover, we highlight the multiple compounds that target E3 ubiquitin ligases or deubiquitinases to influence osteoarthritis progression. We discuss the challenge and future perspectives modulation of E3 ubiquitin ligases and deubiquitinases expression for enhancement of the therapeutic efficacy in osteoarthritis patients. We conclude that modulating ubiquitination and deubiquitination could alleviate the osteoarthritis pathogenesis to achieve the better treatment outcomes in osteoarthritis patients.
Topics: Humans; Aged; Ubiquitination; Ubiquitin-Protein Ligases; Deubiquitinating Enzymes; Osteoarthritis; Ubiquitins
PubMed: 37359559
DOI: 10.3389/fimmu.2023.1217466 -
Journal of Cancer 2021The process of ubiquitination and deubiquitination is widely present in the human body's protein reactions and plays versatile roles in multiple diseases.... (Review)
Review
The process of ubiquitination and deubiquitination is widely present in the human body's protein reactions and plays versatile roles in multiple diseases. Deubiquitinating enzymes (DUBs) are significant regulators of this process, which cleave the ubiquitin (Ub) moiety from various substrates and maintain protein stability. Lung adenocarcinoma (LUAD) is the most common type of non-small cell lung cancer (NSCLC) and remains refractory to treatment. To elucidate the mechanism of LUAD and advance new therapeutic targets, we review the latest research progress on DUBs in LUAD. We summarize the biological capabilities of these DUBs and further highlight those DUBs that may serve as anticancer target candidates for precision treatment. We also discuss deubiquitinase inhibitors, which are expected to play a role in targeted LUAD therapy.
PubMed: 34405018
DOI: 10.7150/jca.56532 -
Cancer Cell International 2017Cancer stem cells (CSCs) are rare but accounted for tumor initiation, progression, metastasis, relapse and therapeutic resistance. Ubiquitination and deubiquitination of... (Review)
Review
Cancer stem cells (CSCs) are rare but accounted for tumor initiation, progression, metastasis, relapse and therapeutic resistance. Ubiquitination and deubiquitination of stemness-related proteins are essential for CSC maintenance and differentiation, even leading to execute various stem cell fate choices. Deubiquitinating enzymes (DUBs), specifically disassembling ubiquitin chains, are important to maintain the balance between ubiquitination and deubiquitination. In this review, we have focused on the DUBs regulation of stem cell fate determination. For example, we discuss deubiquitinase inhibition may lead stem cell transcription factors and CSCs-related protein degradation. Also, CSCs microenvironment is regulated by DUBs activity. Our review provides a new insight into DUBs activity by emphasizing their cellular role in regulating stem cell fate and illustrates the opportunities for the application of DUBs inhibitors in the CSC-targeted therapy.
PubMed: 29142505
DOI: 10.1186/s12935-017-0472-0