EWSR1::ATF1 hyperactivation via TRIM11 depletion triggers lethal metabolic rewiring in clear cell sarcoma

TRIM11 depletion hyperactivates EWSR1::ATF1 in clear cell sarcoma cells, causing lethal metabolic rewiring driven by cataplerotic carbon withdrawal and impaired oxidative phosphorylation.

• Why it matters: CCS lacks effective, well-tolerated therapies, and fusion transcription factors are hard to inhibit directly; targeting UPS-controlled fusion abundance could expose vulnerabilities.
• What they did: Using a reporter-based CRISPR/Cas9 knockout screen of UPS components, the study identified TRIM11 as an E3 ligase regulating EWSR1::ATF1 turnover, then linked lethal effects to PCK1 via proteomics and metabolic assays.
• The result: TRIM11 loss increased nuclear fusion protein, amplified fusion transcription, and reduced viability; PCK1 mediated the lethal phenotype, and high PCK1 expression in patient tumors associated with metastatic programs and shorter survival.

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