論文 - 詳細
| RRC ID | 86202 |
|---|---|
| 著者 | Floros KV, Fairchild CK Jr, Li J, Zhang K, Roberts JL, Kurupi R, Paudel D, Xing Y, Hu B, Kraskauskiene V, Hosseini N, Shen S, Inge MM, Smith-Fry K, Li L, Sotiriou A, Dalton KM, Jose A, Abdelfadiel EI, Hill RD, Slaughter JM, Shende M, Lorenz MR, Tanaka N, Kajino T, Nelson ML, Hinojosa MR, Kehinde VA, Belvin BR, Sugiokto FG, Lai Z, Dimopoulos AC, Boikos SA, Stamatouli AM, Lewis JP, Manjili MH, Ebi H, Valerie K, Li R, Poklepovic A, Koblinski JE, Siggers T, Banito A, Dozmorov MG, Jones KB, Radhakrishnan SK, Faber AC. |
| タイトル | Targeting SUMOylation promotes cBAF complex stabilization and disruption of the SS18::SSX transcriptome in synovial sarcoma. |
| ジャーナル | Nat Commun |
| Abstract |
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) complexes and amplified expression of SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) complexes that drive an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program. The small molecule SUMOylation inhibitor, TAK-981, de-SUMOylates the cBAF/PBAF component, SMARCE1, stabilizing and restoring cBAF on chromatin, shifting SS models away from SS18::SSX-driven transcription. The result is DNA damage, cell death and tumor inhibition across both human and mouse SS tumor models. TAK-981 synergizes 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 an unappreciated role of SUMOylation in SS and a subsequent therapeutic vulnerability. |
| 巻・号 | 16(1) |
| ページ | 9761 |
| 公開日 | 2025-11-5 |
| DOI | 10.1038/s41467-025-64665-8 |
| PII | 10.1038/s41467-025-64665-8 |
| PMID | 41193430 |
| PMC | PMC12589557 |
| MeSH | Animals Cell Line, Tumor Chromatin Assembly and Disassembly Chromosomal Proteins, Non-Histone* / genetics Chromosomal Proteins, Non-Histone* / metabolism DNA Damage / drug effects DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism Gene Expression Regulation, Neoplastic / drug effects Humans Mice Neoplasm Proteins* / genetics Neoplasm Proteins* / metabolism Oncogene Proteins, Fusion* / genetics Oncogene Proteins, Fusion* / metabolism Repressor Proteins* / genetics Repressor Proteins* / metabolism Sarcoma, Synovial* / drug therapy Sarcoma, Synovial* / genetics Sarcoma, Synovial* / metabolism Sarcoma, Synovial* / pathology Sumoylation* / drug effects Transcription Factors / genetics Transcription Factors / metabolism Transcriptome* |
| IF | 12.121 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | News |
| 各媒体での言及数の合計 | 8 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | Aska-SS(RCB3576) HS-SY-II(RCB2231) Yamato-SS(RCB3577) |