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USP22 overexpression leads to aberrant signal transduction but is not sufficient to drive tumor formation in mice

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE180005 | GEO | 2021/08/13

REPOSITORIES: GEO

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Usp22 controls multiple signaling pathways that are essential for vasculature formation in the mouse placenta

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.

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The SAGA complex regulates early steps in transcription via its deubiquitylase module subunit USP22

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.

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The SAGA complex regulates early steps in transcription via its deubiquitylase module subunit USP22

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USP22 supports the aggressive behavior of basal-like breast cancer by stimulating cellular respiration

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The deubiquitinase USP22 stabilizes BMI1 polycomb ring finger oncoprotein to confer cancer stem cell traits and glioblastoma progression

Project description:Glioblastoma (GBM) is the most common and aggressive primary brain tumor with limited therapeutic options, possibly because of the highly tumorigenic subpopulations of stem cell-like cells. Mechanisms that sustain cancer stem cells are crucial to tumor progression. The polycomb group protein BMI1 (BMI1 proto-oncogene, polycomb ring finger) maintains cancer hallmarks including the glioblastoma stem-like cell (GSC) state. Ubiquitin-specific protease 22 (USP22) is highly expressed in and required for the maintenance of cancer stem cells (CSCs). Previously, we observed that forced expressed microRNA-218 in glioblastoma cells led to suppressed BMI1 expression. However, the pathways engaged by USP22 or driving BMI1 accumulation in GSCs remained elusive. Here, we found USP22 to be a novel deubiquitylase of BMI1. USP22 directly deubiquitylates and stabilizes BMI1. USP22 protein levels are elevated in tumor neurosphere. USP22 depletion induces BMI1 destabilization, and results in the inhibition of GSCs self-renewal by regulating a broad range of genes involved in glioma stemness and progression. Xenograft analyses using U87MG cells showed that both USP22 and BMI1 depletion attenuated tumor growth. Clinically, the expression levels of USP22 and BMI1 were positively correlated with those common targets like POSTN, HEY2, or PDGFRA and inversely correlated with ATF3 in human glioblastoma specimens. Taken together, our data reveals that USP22 functions as a novel deubiquitylase of BMI1 and inhibits self-renewal of GSCs by stabilizing BMI1. These findings also indicate that the USP22-BMI1 axis has a critical role in glioma tumorigenesis and that targeting the axis may provide a new therapeutic approach for human glioblastoma.

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