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Targeting SUMO2 reverses aberrant epigenetic rewiring driven by SS18::SSX fusion oncoproteins and impairs sarcomagenesis [CRISPR Screening]

ABSTRACT: Targeting SUMO2 reverses aberrant epigenetic rewiring driven by SS18::SSX fusion oncoproteins and impairs sarcomagenesis [CRISPR Screening]

PROVIDER: PRJNA1147696 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30223780_1.fastq.gz	Fastqsanger.gz
	SRR30223780_2.fastq.gz	Fastqsanger.gz
	SRR30223781_1.fastq.gz	Fastqsanger.gz
	SRR30223781_2.fastq.gz	Fastqsanger.gz
	SRR30223782_1.fastq.gz	Fastqsanger.gz

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Targeting SUMO2 reverses aberrant epigenetic rewiring driven by SS18::SSX fusion oncoproteins and impairs sarcomagenesis [CRISPR Screening]

Project description:Synovial sarcoma (SySa) is an aggressive soft tissue sarcoma with an urgent need to develop targeted therapies. Here, we exploited specific vulnerabilities created by transcriptional rewiring by the fusion protein SS18::SSX, the sole oncogenic driver in SySa. To uncover genes that are selectively essential for the fitness of SySa cells compared to other tumor cell lines, we mined the Cancer-Dependency-Map data. Targeted CRISPR library screening of SySa-selective candidates revealed that the small ubiquitin-like modifier 2 (SUMO2) constituted one of the strongest dependencies both in vitro and in vivo. TAK-981, a clinical-stage small-molecule SUMO2 inhibitor potently suppressed growth and colony-forming ability. Transcriptomic profiling showed that SUMO2 inhibition elicited a profound reversal of the gene expression program orchestrated by SS18::SSX fusion. Further, genetic depletion or SUMO2 inhibition reduced global expression levels and chromatin occupancy of the SS18::SSX fusion protein with a concomitant reduction in histone 2A lysine 119 ubiquitination (H2AK119ub), an epigenetic mark facilitating SySa pathogenesis. Taken together, our study identifies SUMO2 as a novel, selective vulnerability in synovial sarcoma, suggesting new avenues for targeted treatment of soft tissue tumors.

2024-11-06 | GSE274712 | GEO

Targeting SUMO2 reverses aberrant epigenetic rewiring driven by SS18::SSX fusion oncoproteins and impairs sarcomagenesis [CUT&RUN]

2024-11-06 | GSE276071 | GEO

Targeting SUMO2 reverses aberrant epigenetic rewiring driven by SS18::SSX fusion oncoproteins and impairs sarcomagenesis [ChIP-seq]

2024-11-06 | GSE276068 | GEO

Targeting SUMO2 reverses aberrant epigenetic rewiring driven by SS18::SSX fusion oncoproteins and impairs sarcomagenesis [RNA-seq]

2024-11-06 | GSE276073 | GEO

Targeting SUMO2 reverses aberrant epigenetic rewiring driven by SS18::SSX fusion oncoproteins and impairs sarcomagenesis

Project description:Targeting SUMO2 reverses aberrant epigenetic rewiring driven by SS18::SSX fusion oncoproteins and impairs sarcomagenesis

| PRJNA1154630 | ENA

Targeting SUMO2 reverses aberrant epigenetic rewiring driven by SS18::SSX fusion oncoproteins and impairs sarcomagenesis [RNA-seq]

Project description:Targeting SUMO2 reverses aberrant epigenetic rewiring driven by SS18::SSX fusion oncoproteins and impairs sarcomagenesis [RNA-seq]

| PRJNA1154640 | ENA

Targeting SUMO2 reverses aberrant epigenetic rewiring driven by SS18::SSX fusion oncoproteins and impairs sarcomagenesis [CUT&RUN]

Project description:Targeting SUMO2 reverses aberrant epigenetic rewiring driven by SS18::SSX fusion oncoproteins and impairs sarcomagenesis [CUT&RUN]

| PRJNA1154645 | ENA

Targeting SUMO2 reverses aberrant epigenetic rewiring driven by SS18::SSX fusion oncoproteins and impairs sarcomagenesis [ChIP-seq]

Project description:Targeting SUMO2 reverses aberrant epigenetic rewiring driven by SS18::SSX fusion oncoproteins and impairs sarcomagenesis [ChIP-seq]

| PRJNA1154633 | ENA

Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma

Project description:Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF/PBAF component, SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-driven transcription, resulting in DNA damage, cell death and tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX transcriptome, identifying a therapeutic vulnerability in SS.

2025-08-07 | PXD059936 | Pride

A stage-specific induction system reveals that the oncogenic fusion protein in synovial sarcoma, SS18-SSX, is a cellular context-dependent epigenetic modifier

Project description:We analyzed the effects of cellular context on the function of the synovial sarcoma-specific fusion protein, SS18-SSX, using human pluripotent stem cells containing the drug-inducible SS18-SSX gene. To investigate the cell-type-dependent effecfts of SS18-SSX, we performed gene expression profiling experiments. Comparison of global gene expressions of hPSCs, hPSC-NCCs, and hPSC-MSCs with or without the inductuion of SS18-SSX2

2016-04-13 | E-GEOD-63895 | biostudies-arrayexpress

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