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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276074 | GEO | 2024/11/06

REPOSITORIES: GEO

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SUMO2 Inhibition Reverses Aberrant Epigenetic Rewiring Driven by Synovial Sarcoma Fusion Oncoproteins and Impairs Sarcomagenesis.

Project description:Synovial Sarcoma (SySa) is an aggressive soft tissue sarcoma that accounts for 5 - 10% of all soft tissue sarcomas. Current treatment involves radiation and radical surgery including limb amputation, highlighting the urgent need to develop targeted therapies. We reasoned that transcriptional rewiring by the fusion protein SS18-SSX, the sole oncogenic driver in SySa, creates specific vulnerabilities that can be exploited for treatment. To uncover genes that are selectively essential for SySa, we mined The Cancer Dependency Map (DepMap) data to identify genes that specifically impact the fitness of SySa compared to other tumor cell lines. Targeted CRISPR library screening of SySa-selective candidates revealed that the small ubiquitin-like modifier 2 (SUMO2) was one of the strongest dependencies both in vitro as well as in vivo. TAK-981, a clinical-stage small molecule SUMO2 inhibitor potently inhibited growth and colony-forming ability. Strikingly, transcriptomic studies showed that pharmacological SUMO2 inhibition with TAK-981 treatment elicited a profound reversal of a gene expression program orchestrated by SS18-SSX fusions. Of note, genetic or pharmacological SUMO2 inhibition reduced global and chromatin levels of the SS18-SSX fusion protein with a concomitant reduction in histone 2A lysine 119 ubiquitination (H2AK119ub), an epigenetic mark that plays an important role in SySa pathogenesis. Taken together, our studies identify SUMO2 as a novel, selective vulnerability in SySa. Since SUMO2 inhibitors are currently in Phase 1/2 clinical trials for other cancers, our findings present a novel avenue for targeted treatment of synovial sarcoma.

| S-EPMC11463515 | biostudies-literature

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 [RNA-seq]

2024-11-06 | GSE276073 | 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

SUMO2 Inhibition Reverses Aberrant Epigenetic Rewiring Driven by Synovial Sarcoma Fusion Oncoproteins and Impairs Sarcomagenesis

Project description:SUMO2 Inhibition Reverses Aberrant Epigenetic Rewiring Driven by Synovial Sarcoma Fusion Oncoproteins and Impairs Sarcomagenesis

| PRJNA1154630 | ENA

SUMO2 Inhibition Reverses Aberrant Epigenetic Rewiring Driven by Synovial Sarcoma Fusion Oncoproteins and Impairs Sarcomagenesis [CRISPR Screening]

Project description:SUMO2 Inhibition Reverses Aberrant Epigenetic Rewiring Driven by Synovial Sarcoma Fusion Oncoproteins and Impairs Sarcomagenesis [CRISPR Screening]

| PRJNA1147696 | ENA

SUMO2 Inhibition Reverses Aberrant Epigenetic Rewiring Driven by Synovial Sarcoma Fusion Oncoproteins and Impairs Sarcomagenesis [CUT&RUN]

Project description:SUMO2 Inhibition Reverses Aberrant Epigenetic Rewiring Driven by Synovial Sarcoma Fusion Oncoproteins and Impairs Sarcomagenesis [CUT&RUN]

| PRJNA1154645 | ENA

SUMO2 Inhibition Reverses Aberrant Epigenetic Rewiring Driven by Synovial Sarcoma Fusion Oncoproteins and Impairs Sarcomagenesis [ChIP-seq]

Project description:SUMO2 Inhibition Reverses Aberrant Epigenetic Rewiring Driven by Synovial Sarcoma Fusion Oncoproteins and Impairs Sarcomagenesis [ChIP-seq]

| PRJNA1154633 | ENA

SUMO2 Inhibition Reverses Aberrant Epigenetic Rewiring Driven by Synovial Sarcoma Fusion Oncoproteins and Impairs Sarcomagenesis [RNA-seq]

Project description:SUMO2 Inhibition Reverses Aberrant Epigenetic Rewiring Driven by Synovial Sarcoma Fusion Oncoproteins and Impairs Sarcomagenesis [RNA-seq]

| PRJNA1154640 | ENA

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