USP22 functions as an oncogenic driver in prostate cancer by regulating cell proliferation and DNA repair
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE140164 | GEO | 2020/01/16
REPOSITORIES: GEO
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Project description:Emerging evidence indicates the deubiquitinase USP22 regulates transcriptional activation and modification of target substrates to promote pro-oncogenic phenotypes. Here, in vivo characterization of tumor-associated USP22 upregulation and unbiased interrogation of USP22-regulated functions in vitro demonstrated critical roles for USP22 in prostate cancer. Specifically, clinical datasets validated that USP22 expression is elevated in prostate cancer, and a novel murine model demonstrated a hyperproliferative phenotype with prostate-specific USP22 overexpression. Accordingly, upon overexpression or depletion of USP22, enrichment of cell-cycle and DNA repair pathways was observed in the USP22-sensitive transcriptome and ubiquitylome using prostate cancer models of clinical relevance. Depletion of USP22 sensitized cells to genotoxic insult, and the role of USP22 in response to genotoxic insult was further confirmed using mouse adult fibroblasts from the novel murine model of USP22 expression. As it was hypothesized that USP22 deubiquitylates target substrates to promote protumorigenic phenotypes, analysis of the USP22-sensitive ubiquitylome identified the nucleotide excision repair protein, XPC, as a critical mediator of the USP22-mediated response to genotoxic insult. Thus, XPC undergoes deubiquitylation as a result of USP22 function and promotes USP22-mediated survival to DNA damage. Combined, these findings reveal unexpected functions of USP22 as a driver of protumorigenic phenotypes and have significant implications for the role of USP22 in therapeutic outcomes. SIGNIFICANCE: The studies herein present a novel mouse model of tumor-associated USP22 overexpression and implicate USP22 in modulation of cellular survival and DNA repair, in part through regulation of XPC.
| S-EPMC7814394 | biostudies-literature
Project description:Somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) by overexpressing OCT4, SOX2, KLF4 and MYC. Although this cell fate transition is a slow and inefficient process, inhibiting several epigenetic barriers has shown to facilitate it. A previously employed epigenetic focused CRISPR-Cas9-mediated knockout screen during reprogramming uncovered novel human somatic cell reprogramming barriers. Here, I showed that USP22, target for gRNAs that were enriched in iPSCs from the screen, is a barrier for reprogramming and its loss is compatible with iPSC generation. Overexpressing wild-type or deubiquitinase mutant (C185A) USP22 in knockout background could rescue the phenotype. Additionally, knocking out other SAGA deubiquitinase subunits, ENY2 and ATXN7L3 did not increase the reprogramming efficiency. Mechanistically, we showed that USP22 loss upregulates an important pluripotency-related transcription factor, SOX2, expression even as early as 3 days after OSKM expression. We hypothesized that USP22 downregulates pluripotency-related gene expression during reprogramming independent from its SAGA integration and deubiquitinase activity. To address this, I will repeat rescuing USP22 knockout phenotype in reprogramming by overexpressing mutant versions of USP22 including K129R (acetyl inhibited) and HHAA (deubiqutinase). Additionally, I will check the expression of pluripotency-related genes at early time points of reprogramming upon USP22 knockout by transcriptome profiling. Lastly, I will generate USP22 knockout iPSC lines to force them to differentiation to observe if they have any problem with pluripotency exit. This work will establish a mechanistic understanding for the role USP22 play on both human somatic cell reprogramming, pluripotency and differentiation.
2023-07-31 | GSE225151 | GEO
Project description:Dynamic control of ubiquitination by deubiquitinating enzymes is essential for almost all biological processes. Ubiquitin-specific peptidase 22 (USP22) is part of the SAGA complex and catalyzes the removal of monoubiquitination from histone H2B, thereby regulating gene transcription. However, novel roles for USP22 have recently emerged, such as tumor development and cell death. Apart from apoptosis, the relevance of USP22 in other programmed cell death pathways still remains unclear. Here, we describe a novel role for USP22 in controlling necroptotic cell death in a variety of tumor cell lines. Loss of USP22 expression significantly delays TNF/Smac mimetic/zVAD.fmk (TBZ)-induced necroptosis, without affecting TNF-mediated NF-B activation or extrinsic apoptosis. Mass-spectrometric ubiquitin remnant profiling identified lysine 518 of Receptor-interacting protein kinase 3 (RIPK3) as USP22-dependent ubiquitination target during necroptosis induction. Mutation of K518 in RIPK3 reduced necroptosisassociated RIPK3 ubiquitination and amplified necrosome formation and necroptotic cell death. In conclusion, we identify a novel role of USP22 in necroptosis and further elucidate the relevance of ubiquitination as crucial regulator of necroptotic cell death.
2021-05-03 | PXD020909 | Pride
Project description:USP22 functions as an oncogenic driver in prostate cancer by regulating cell proliferation and DNA repair
| PRJNA588452 | ENA
Project description:Usp22, a component of the SAGA complex, is over expressed in highly aggressive cancers, but the normal functions of this deubiquitinase are not well defined. We determined that loss of Usp22 in mice results in embryonic lethality due to defects in extra-embryonic placental tissues and failure to establish proper vascular interactions with the maternal circulatory system. These phenotypes arise from abnormal gene expression patterns that reflect defective kinase signaling, including TGFβ and several receptor tyrosine kinase (RTK) pathways. Usp22 deletion in endothelial cells and pericytes induced from embryonic stem cells also hinders these signaling cascades with detrimental effects on cell survival and differentiation as well as ability to form vessels. Our findings provide new insights to Usp22 functions during development that may offer clues to its role in disease states.
2019-02-04 | GSE126069 | GEO
Project description:SAGA is a modular cofactor complex that is essential for eukaryotic transcription. SAGA’s complement of ~20 proteins exist within four structurally and functionally distinct modules, two of which are catalytic. Within the KAT module, GCN5 acetylates histone tails, leading to increased chromatin accessibility and bromodomain protein recruitment. The DUB module contains the ubiquitin hydrolase USP22. In yeast, the USP22 ortholog deubiquitylates H2B, resulting in Pol II S2 phosphorylation and subsequent transcriptional elongation. We report here that metazoan SAGA, and USP22 specifically, are required at a more proximal stage in activator-driven transcription, i.e. pre-initiation complex (PIC) assembly. A combination of genome-wide and proteomic analyses revealed that H2B deubiquitylation is not linked to USP22-dependent transcription. Instead, USP22 controls Mediator tail subunit ubiquitylation. Mechanistically, USP22 controls loading of Mediator tail and GTFs onto promoters, with Mediator core recruitment being USP22-independent. These findings place human SAGA function at the earliest steps in activator-driven transcription.
2021-04-12 | GSE158108 | GEO
Project description:SAGA is a modular cofactor complex that is essential for eukaryotic transcription. SAGA’s complement of ~20 proteins exist within four structurally and functionally distinct modules, two of which are catalytic. Within the KAT module, GCN5 acetylates histone tails, leading to increased chromatin accessibility and bromodomain protein recruitment. The DUB module contains the ubiquitin hydrolase USP22. In yeast, the USP22 ortholog deubiquitylates H2B, resulting in Pol II S2 phosphorylation and subsequent transcriptional elongation. We report here that metazoan SAGA, and USP22 specifically, are required at a more proximal stage in activator-driven transcription, i.e. pre-initiation complex (PIC) assembly. A combination of genome-wide and proteomic analyses revealed that H2B deubiquitylation is not linked to USP22-dependent transcription. Instead, USP22 controls Mediator tail subunit ubiquitylation. Mechanistically, USP22 controls loading of Mediator tail and GTFs onto promoters, with Mediator core recruitment being USP22-independent. These findings place human SAGA function at the earliest steps in activator-driven transcription.
2019-10-24 | GSE121798 | GEO
Project description:Within the context of the DUB module in the SAGA complex, USP22 is involved in transcriptional elongation through the regulation of H2AK119ub1 and H2BK120ub1. However, up till now, the spectrum of USP22-regulated target genes largely remains unclear, partially due to organism-, cell- and context-dependent redundancy in alternative DUBs that might compensate for loss of USP22. To understand which genes are regulated by USP22, we profiled USP22-dependent changes in gene expression in the human intestinal epithelial cell (hIEC) line HT-29.
2022-08-22 | GSE190036 | GEO
Project description:USP22 overexpression is observed in several human cancers and is correlated with poor patient outcomes. The molecular basis underlying this correlation is not clear. USP22 is the catalytic subunit of the deubiquitylation module in the SAGA histone modifying complex, which regulates gene transcription. Our previous work demonstrated that loss of USP22 in mice leads to decreased expression of several components of receptor tyrosine kinase and TGFβ signaling pathways. To determine whether these pathways are upregulated when USP22 is overexpressed, we created a mouse model that expresses high levels of USP22 in all tissues. Phenotypic characterization of these mice revealed over branching of the mammary glands in females. Transcriptomic analyses indicate upregulation of key pathways involved in mammary gland branching in mammary epithelial cells derived from the USP22 overexpressing mice, including estrogen receptor, ERK/MAPK and TGFβ signaling. However, USP22 overexpression did not lead to increased tumorigenesis in any tissue. Our findings indicate that elevated levels of USP22 are not sufficient to induce tumors but it may enhance signaling abnormalities associated with oncogenesis.
2021-08-13 | GSE180005 | GEO
Project description:Emergency hematopoiesis is a concerted response geared towards enhanced protection from infection, involving multiple cell types and developmental stages across the immune system. Despite its importance, the underlying molecular regulation remains poorly understood. The deubiquitinase USP22 regulates the levels of monoubiquitinated histone H2B (H2Bub1), which is involved in intracellular interferon responses. Here we show that, in the absence of infection or inflammation, mice lacking Usp22 in blood and immune cells display profound systemic emergency hematopoiesis, evident by increased hematopoietic stem cell proliferation, myeloid bias, and extramedullary hematopoiesis. Functionally, loss of Usp22 results in elevated phagocytosis by neutrophilic granulocytes, and enhanced innate protection against Listeria monocytogenes infection. At the molecular level, we find this state of emergency hematopoiesis associated with transcriptional signatures of myeloid priming, enhanced mitochondrial respiration, as well as innate and adaptive immunity and inflammation. Augmented inflammatory gene expression was linked to elevated locus-specific H2Bub1 levels. Collectively, a tunable epigenetic state promotes systemic emergency hematopoiesis in a cell-autonomous manner and enhances innate protection, paving potential ways towards immune enhancement.
2022-11-02 | GSE212758 | GEO