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Loss of the USP22 deubiquitylase confers resistance to chemotherapy in small cell lung cancer [RNA-seq]

ABSTRACT: Loss of the USP22 deubiquitylase confers resistance to chemotherapy in small cell lung cancer [RNA-seq]

PROVIDER: PRJNA1257930 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR33403377.fastq.gz	Fastqsanger.gz
	SRR33403378.fastq.gz	Fastqsanger.gz
	SRR33403379.fastq.gz	Fastqsanger.gz
	SRR33403380.fastq.gz	Fastqsanger.gz
	SRR33403381.fastq.gz	Fastqsanger.gz

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Loss of the USP22 deubiquitylase confers resistance to chemotherapy in small cell lung cancer [CUT&Tag]

Project description:Small cell lung cancer (SCLC) responds exceptionally well to cytotoxic chemotherapy. However, relapse with the emergence of chemoresistant disease is rapid and accompanied by poor treatment outcomes. To understand the genetic basis of chemoresistance in SCLC, we applied in vivo CRISPR deletion screening to patient-derived xenograft (PDX) models. Top screen hits included genes encoding components of the transcriptional co-activator SAGA (Spt-Ada-Gcn5 acetyltransferase) complex. We demonstrate that deletion of the SAGA deubiquitylase USP22 conferred cisplatin/etoposide resistance in two chemosensitive PDX models, and that restoring expression in a PDX model harboring homozygous truncating mutation of USP22 re-sensitized tumors to chemotherapy. USP22 loss increased gene body histone H2A-K119 monoubiquitylation in genes encoding key regulators of neuronal differentiation, and suppressed neural and neuroendocrine gene expression including targets of ASCL1. Chemoresistance following USP22 loss reflected attenuated DNA damage-driven phosphorylation events and apoptosis, in conjunction with increased expression of glycolysis and hypoxia-related genes. Glycolysis program upregulation may reflect a targetable vulnerability, as inhibition of GLUT1 re-sensitized USP22-null tumors to chemotherapy.

2025-05-08 | GSE296258 | GEO

Loss of the USP22 deubiquitylase confers resistance to chemotherapy in small cell lung cancer [RNA-seq]

2025-05-08 | GSE296155 | GEO

Loss of the USP22 deubiquitylase confers resistance to chemotherapy in small cell lung cancer

Project description:Loss of the USP22 deubiquitylase confers resistance to chemotherapy in small cell lung cancer

| PRJNA1258286 | ENA

Loss of the USP22 deubiquitylase confers resistance to chemotherapy in small cell lung cancer [CUT&Tag]

Project description:Loss of the USP22 deubiquitylase confers resistance to chemotherapy in small cell lung cancer [CUT&Tag]

| PRJNA1258284 | ENA

Loss of the USP22 deubiquitylase confers resistance to chemotherapy in small cell lung cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2025-05-08 | GSE296261 | GEO

An in vivo screening platform using PDX models reveals KEAP1, USP22 and other drivers of chemoresistance in small cell lung cancer

Project description:Small cell lung cancer (SCLC) is characterized by exquisite chemosensitivity followed by rapid emergence of chemoresistance. To identify genetic events that drive resistance to cisplatin-etoposide chemotherapy, we conducted cDNA overexpression and CRISPR knockout screens in an in vivo platform centered on chemosensitive patient derived xenograft (PDX) models of SCLC. cDNA overexpression screens revealed MYC, MYCN and MYCL as drivers of tumor cell growth through chemotherapy. CRISPR knockout screens identified the KEAP1/NRF2 pathway and members of the SAGA (Spt-Ada-Gcn5 acetyltransferase) complex, including the deubiquitylase USP22. We demonstrated that knockout of either KEAP1 or USP22 switches chemosensitive PDX models to become chemoresistant, with our data supporting distinct molecular consequences of each, including suppression of DNA damage signaling upon USP22 deletion. Data from the IMpower133 clinical trial revealed that a substantial proportion of SCLC patients exhibit KEAP1/NFE2L2 genetic alterations, with activation of an NRF2 transcriptional signature associated with reduced SCLC patient survival with chemotherapy.

2025-03-11 | GSE255095 | GEO

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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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.

2017-01-01 | GSE89239 | GEO

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

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

| PRJNA664023 | ENA