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SUMO2 Inhibition Reverses Aberrant Epigenetic Rewiring Driven by Synovial Sarcoma 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 [CRISPR Screening]

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 Dependency Maps (Depmap) database to identify genes that specifically impact the fitness of SySa compared to other tumor cell lines. Targeted CRISPR library screening of select 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, colony-forming ability, and spheroid formation of SySa cell lines. Strikingly, transcriptomic studies showed that 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 is enhanced by the SySa fusions and 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 human cancer, our findings present a novel potential avenue for targeted treatment of synovial sarcoma.

2024-11-06 | GSE274712 | GEO

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

2024-11-06 | GSE276073 | GEO

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

2024-11-06 | GSE276071 | GEO

SUMO2 Inhibition Reverses Aberrant Epigenetic Rewiring Driven by Synovial Sarcoma 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 [RNA-seq]

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

| PRJNA1154640 | 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

Downstream and intermediate interactions of synovial sarcoma-associated fusion oncoproteins and their implication for targeted therapy.

Project description:Synovial sarcoma (SS), an aggressive type of soft tissue tumor, occurs mostly in adolescents and young adults. The origin and molecular mechanism of the development of SS remain only partially known. Over 90% of SS cases are characterized by the t(X;18)(p11.2;q11.2) translocation, which results mainly in the formation of SS18-SSX1 or SS18-SSX2 fusion genes. In recent years, several reports describing direct and indirect interactions of SS18-SSX1/SSX2 oncoproteins have been published. These reports suggest that the fusion proteins particularly affect the cell growth, cell proliferation, TP53 pathway, and chromatin remodeling mechanisms, contributing to SS oncogenesis. Additional research efforts are required to fully explore the protein-protein interactions of SS18-SSX oncoproteins and the pathways that are regulated by these partnerships for the development of effective targeted therapy.

| S-EPMC3329658 | biostudies-literature

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