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Nature Reviews. Cancer Dec 2023Ubiquitination is an essential regulator of most, if not all, signalling pathways, and defects in cellular signalling are central to cancer initiation, progression and,... (Review)
Review
Ubiquitination is an essential regulator of most, if not all, signalling pathways, and defects in cellular signalling are central to cancer initiation, progression and, eventually, metastasis. The attachment of ubiquitin signals by E3 ubiquitin ligases is directly opposed by the action of approximately 100 deubiquitinating enzymes (DUBs) in humans. Together, DUBs and E3 ligases coordinate ubiquitin signalling by providing selectivity for different substrates and/or ubiquitin signals. The balance between ubiquitination and deubiquitination is exquisitely controlled to ensure properly coordinated proteostasis and response to cellular stimuli and stressors. Not surprisingly, then, DUBs have been associated with all hallmarks of cancer. These relationships are often complex and multifaceted, highlighted by the implication of multiple DUBs in certain hallmarks and by the impact of individual DUBs on multiple cancer-associated pathways, sometimes with contrasting cancer-promoting and cancer-inhibiting activities, depending on context and tumour type. Although it is still understudied, the ever-growing knowledge of DUB function in cancer physiology will eventually identify DUBs that warrant specific inhibition or activation, both of which are now feasible. An integrated appreciation of the physiological consequences of DUB modulation in relevant cancer models will eventually lead to the identification of patient populations that will most likely benefit from DUB-targeted therapies.
Topics: Humans; Ubiquitination; Ubiquitin; Neoplasms; Ubiquitin-Protein Ligases; Deubiquitinating Enzymes
PubMed: 37935888
DOI: 10.1038/s41568-023-00633-y -
Nature Apr 2024Targeted protein degradation and stabilization are promising therapeutic modalities because of their potency, versatility and their potential to expand the druggable...
Targeted protein degradation and stabilization are promising therapeutic modalities because of their potency, versatility and their potential to expand the druggable target space. However, only a few of the hundreds of E3 ligases and deubiquitinases in the human proteome have been harnessed for this purpose, which substantially limits the potential of the approach. Moreover, there may be other protein classes that could be exploited for protein stabilization or degradation, but there are currently no methods that can identify such effector proteins in a scalable and unbiased manner. Here we established a synthetic proteome-scale platform to functionally identify human proteins that can promote the degradation or stabilization of a target protein in a proximity-dependent manner. Our results reveal that the human proteome contains a large cache of effectors of protein stability. The approach further enabled us to comprehensively compare the activities of human E3 ligases and deubiquitinases, identify and characterize non-canonical protein degraders and stabilizers and establish that effectors have vastly different activities against diverse targets. Notably, the top degraders were more potent against multiple therapeutically relevant targets than the currently used E3 ligases cereblon and VHL. Our study provides a functional catalogue of stability effectors for targeted protein degradation and stabilization and highlights the potential of induced proximity screens for the discovery of new proximity-dependent protein modulators.
Topics: Humans; Deubiquitinating Enzymes; Protein Stability; Proteolysis; Proteome; Proteomics; Ubiquitin-Protein Ligases; Substrate Specificity; Proteolysis Targeting Chimera; Von Hippel-Lindau Tumor Suppressor Protein
PubMed: 38509365
DOI: 10.1038/s41586-024-07224-3 -
Nature Communications Oct 2023Colorectal cancer (CRC) patients with liver metastases usually obtain less benefit from immunotherapy, and the underlying mechanisms remain understudied. Here, we...
Colorectal cancer (CRC) patients with liver metastases usually obtain less benefit from immunotherapy, and the underlying mechanisms remain understudied. Here, we identify that fibrinogen-like protein 1 (FGL1), secreted from cancer cells and hepatocytes, facilitates the progression of CRC in an intraportal injection model by reducing the infiltration of T cells. Mechanistically, tumor-associated macrophages (TAMs) activate NF-ĸB by secreting TNFα/IL-1β in the liver microenvironment and transcriptionally upregulate OTU deubiquitinase 1 (OTUD1) expression, which enhances FGL1 stability via deubiquitination. Disrupting the TAM-OTUD1-FGL1 axis inhibits metastatic tumor progression and synergizes with immune checkpoint blockade (ICB) therapy. Clinically, high plasma FGL1 levels predict poor outcomes and reduced ICB therapy benefits. Benzethonium chloride, an FDA-approved antiseptics, curbs FGL1 secretion, thereby inhibiting liver metastatic tumor growth. Overall, this study uncovers the critical roles and posttranslational regulatory mechanism of FGL1 in promoting metastatic tumor progression, highlighting the TAM-OTUD1-FGL1 axis as a potential target for cancer immunotherapy.
Topics: Humans; Colonic Neoplasms; Liver Neoplasms; Hepatocytes; Rectal Neoplasms; Tumor Microenvironment; Fibrinogen; Ubiquitin-Specific Proteases
PubMed: 37872170
DOI: 10.1038/s41467-023-42332-0 -
Advanced Science (Weinheim,... Nov 2023Hepatocellular carcinoma (HCC) is a lethal and aggressive human malignancy. The present study examins the anti-tumor effects of deubiquitylating enzymes (DUB) inhibitors...
Hepatocellular carcinoma (HCC) is a lethal and aggressive human malignancy. The present study examins the anti-tumor effects of deubiquitylating enzymes (DUB) inhibitors in HCC. It is found that the inhibitor of ubiquitin specific peptidase 8 (USP8) and DUB-IN-3 shows the most effective anti-cancer responses. Targeting USP8 inhibits the proliferation of HCC and induces cell ferroptosis. In vivo xenograft and metastasis experiments indicate that inhibition of USP8 suppresses tumor growth and lung metastasis. DUB-IN-3 treatment or USP8 depletion decrease intracellular cystine levels and glutathione biosynthesis while increasing the accumulation of reactive oxygen species (ROS). Mechanistical studies reveal that USP8 stabilizes O-GlcNAc transferase (OGT) via inhibiting K48-specific poly-ubiquitination process on OGT protein at K117 site, and STE20-like kinase (SLK)-mediated S716 phosphorylation of USP8 is required for the interaction with OGT. Most importantly, OGT O-GlcNAcylates solute carrier family 7, member 11 (SLC7A11) at Ser26 in HCC cells, which is essential for SLC7A11 to import the cystine from the extracellular environment. Collectively, this study demonstrates that pharmacological inhibition or knockout of USP8 can inhibit the progression of HCC and induce ferroptosis via decreasing the stability of OGT, which imposes a great challenge that targeting of USP8 is a potential approach for HCC treatment.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Ferroptosis; Cystine; Endopeptidases; Ubiquitin Thiolesterase; Endosomal Sorting Complexes Required for Transport; Amino Acid Transport System y+
PubMed: 37867237
DOI: 10.1002/advs.202302953 -
The Journal of Clinical Investigation Dec 2023Regulation of tumoral PD-L1 expression is critical to advancing our understanding of tumor immune evasion and the improvement of existing antitumor immunotherapies....
Regulation of tumoral PD-L1 expression is critical to advancing our understanding of tumor immune evasion and the improvement of existing antitumor immunotherapies. Herein, we describe a CRISPR-based screening platform and identified ATXN3 as a positive regulator for PD-L1 transcription. TCGA database analysis revealed a positive correlation between ATXN3 and CD274 in more than 80% of human cancers. ATXN3-induced Pd-l1 transcription was promoted by tumor microenvironmental factors, including the inflammatory cytokine IFN-γ and hypoxia, through protection of their downstream transcription factors IRF1, STAT3, and HIF-2α. Moreover, ATXN3 functioned as a deubiquitinase of the AP-1 transcription factor JunB, indicating that ATNX3 promotes PD-L1 expression through multiple pathways. Targeted deletion of ATXN3 in cancer cells largely abolished IFN-γ- and hypoxia-induced PD-L1 expression and consequently enhanced antitumor immunity in mice, and these effects were partially reversed by PD-L1 reconstitution. Furthermore, tumoral ATXN3 suppression improved the preclinical efficacy of checkpoint blockade antitumor immunotherapy. Importantly, ATXN3 expression was increased in human lung adenocarcinoma and melanoma, and its levels were positively correlated with PD-L1 as well as its transcription factors IRF1 and HIF-2α. Collectively, our study identifies what we believe to be a previously unknown deubiquitinase, ATXN3, as a positive regulator for PD-L1 transcription and provides a rationale for targeting ATXN3 to sensitize checkpoint blockade antitumor immunotherapy.
Topics: Humans; Animals; Mice; Tumor Escape; B7-H1 Antigen; Transcription Factors; Immunotherapy; Lung Neoplasms; Hypoxia; Deubiquitinating Enzymes; Basic Helix-Loop-Helix Transcription Factors; Cell Line, Tumor; Tumor Microenvironment; Ataxin-3; Repressor Proteins
PubMed: 38038129
DOI: 10.1172/JCI167728 -
Nature Genetics Jan 2024Although over 90 independent risk variants have been identified for Parkinson's disease using genome-wide association studies, most studies have been performed in just... (Meta-Analysis)
Meta-Analysis
Although over 90 independent risk variants have been identified for Parkinson's disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson's disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations.
Topics: Humans; Genome-Wide Association Study; Parkinson Disease; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Ubiquitin Thiolesterase
PubMed: 38155330
DOI: 10.1038/s41588-023-01584-8 -
Cancer Research Nov 2023Many studies have provided valuable information about genomic and transcriptomic changes that occur in colorectal cancer. However, protein abundance cannot be reliably...
UNLABELLED
Many studies have provided valuable information about genomic and transcriptomic changes that occur in colorectal cancer. However, protein abundance cannot be reliably predicted by DNA alteration or mRNA expression, which can be partially attributed to posttranscriptional and/or translational regulation of gene expression. In this study, we identified increased translational efficiency (TE) as a hallmark of colorectal cancer by evaluating the transcriptomic and proteomic features of patients with colorectal cancer, along with comparative transcriptomic and ribosome-protected mRNA analysis in colon epithelial cells and colon cancer cells. COP9 signalosome subunit 7B (COPS7B) was among the key genes that consistently showed both significant TE increase and protein elevation without transcriptional alteration in colorectal cancer. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) enhanced the TE of COPS7B mRNA to promote colorectal cancer growth and metastasis. COPS7B was found to be a component of the ribo-interactome that interacted with ribosomes to facilitate ribosome biogenesis and mRNA translation initiation. Collectively, this study revealed the proteomic features of colorectal cancer and highlighted elevated mRNA translation as a hallmark of colorectal cancer. The identification of the IGF2BP3-COPS7B axis underlying the increased protein synthesis rate in colorectal cancer provided a promising therapeutic target to treat this aggressive disease.
SIGNIFICANCE
Increased expression of COPS7B mediated by IGF2BP3 elevates the translational efficiency of genes enriched in mRNA translation and ribosome biogenesis pathways, promoting protein synthesis and driving progression in colorectal cancer.
Topics: Humans; Colonic Neoplasms; Protein Biosynthesis; Proteomics; Ribosomes; RNA, Messenger; COP9 Signalosome Complex; Transcription Factors
PubMed: 37560971
DOI: 10.1158/0008-5472.CAN-23-0557 -
Advanced Science (Weinheim,... Dec 2023Deubiquitylating enzymes (DUBs) maintain relative homeostasis of the cellular ubiquitome by removing the post-translational modification ubiquitin moiety from... (Review)
Review
Deubiquitylating enzymes (DUBs) maintain relative homeostasis of the cellular ubiquitome by removing the post-translational modification ubiquitin moiety from substrates. Numerous DUBs have been demonstrated specificity for cleaving a certain type of ubiquitin linkage or positions within ubiquitin chains. Moreover, several DUBs perform functions through specific protein-protein interactions in a catalytically independent manner, which further expands the versatility and complexity of DUBs' functions. Dysregulation of DUBs disrupts the dynamic equilibrium of ubiquitome and causes various diseases, especially cancer and immune disorders. This review summarizes the Janus-faced roles of DUBs in cancer including proteasomal degradation, DNA repair, apoptosis, and tumor metastasis, as well as in immunity involving innate immune receptor signaling and inflammatory and autoimmune disorders. The prospects and challenges for the clinical development of DUB inhibitors are further discussed. The review provides a comprehensive understanding of the multi-faced roles of DUBs in cancer and immunity.
Topics: Humans; Ubiquitin; Protein Processing, Post-Translational; Neoplasms; Deubiquitinating Enzymes
PubMed: 37888853
DOI: 10.1002/advs.202303807 -
Cell Death and Differentiation Nov 2023In the current study, we have shown that USP51 promotes colorectal cancer stemness and chemoresistance, and high expression of USP51 predicts survival disadvantage in...
In the current study, we have shown that USP51 promotes colorectal cancer stemness and chemoresistance, and high expression of USP51 predicts survival disadvantage in colorectal cancer patients. Mechanically, USP51 directly binds to Elongin C (ELOC) and forms a larger functional complex with VHL E3 ligase (USP51/VHL/CUL2/ELOB/ELOC/RBX1) to regulate the ubiquitin-dependent proteasomal degradation of HIF1A. USP51 efficiently deubiquitinates HIF1A and activates hypoxia-induced gene transcription. Conversely, the activation of HIF1A under hypoxia transcriptionally upregulates the expression of USP51. Thus, USP51 and HIF1A form a positive feedback loop. Further, we found that the SUMOylation of ELOC at K32 inhibits its binding to USP51. SUMO-specific protease 1 (SENP1) mediates the deSUMOylation of ELOC, promoting the binding of USP51 to ELOC and facilitating the deubiquitination and stabilization of HIF1A by USP51. Importantly, USP51 plays a crucial role in promoting the HIF1A and SENP1-dependent proliferation, migration, stemness, and chemoresistance under hypoxia in colorectal cancer. Together, our data revealed that USP51 is an oncogene stabilizing the pro-survival protein HIF1A, offering a potential therapeutic target for colorectal cancer.
Topics: Humans; Drug Resistance, Neoplasm; Ubiquitin-Protein Ligases; Ubiquitin; Hypoxia; Colorectal Neoplasms; Hypoxia-Inducible Factor 1, alpha Subunit; Ubiquitin-Specific Proteases
PubMed: 37816999
DOI: 10.1038/s41418-023-01228-8 -
International Journal of Biological... 2024Deubiquitylating enzymes (DUBs) play an essential role in targeted protein degradation and represent an emerging therapeutic paradigm in cancer. However, their...
Deubiquitylating enzymes (DUBs) play an essential role in targeted protein degradation and represent an emerging therapeutic paradigm in cancer. However, their therapeutic potential in cholangiocarcinoma (CCA) has not been explored. Herein, based on The Cancer Genome Atlas (TCGA) and The Gene Expression Omnibus (GEO) databases, we found that ubiquitin-specific protease 21 (USP21) was upregulated in CCA, high USP21 level was associated with poor prognosis. In vivo and in vitro, we identified USP21 as a master regulator of CCA growth and maintenance, which directly interacted with deubiquitinates and stabilized the heat shock protein 90 (HSP90) through K48-linked deubiquitination, and in turn, this stabilization increased HIF1A expression, thus upregulating key glycolytic enzyme genes ENO2, ENO3, ALDOC, ACSS2, and then promoted aerobic glycolysis, which provided energy for CCA cell proliferation. In addition, USP21 could directly stabilize alpha-Enolase 1 (ENO1) to promote aerobic glycolysis. Furthermore, increased USP21 level enhanced chemotherapy resistance to the gemcitabine-based regimen. Taken together, we identify a USP21-regulated aerobic glycolysis mechanism that involves the USP21/HSP90/HIF1A axis and USP21/ENO1 axis in CCA tumorigenesis, which could serve as a potential target for the treatment of CCA.
Topics: Humans; Cholangiocarcinoma; Cell Proliferation; Phosphopyruvate Hydratase; Bile Ducts, Intrahepatic; Bile Duct Neoplasms; Glycolysis; Cell Line, Tumor; DNA-Binding Proteins; Biomarkers, Tumor; Tumor Suppressor Proteins; Ubiquitin Thiolesterase
PubMed: 38385089
DOI: 10.7150/ijbs.90774