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• W3204451293 abstract "Hypoxia-inducible factor 2α (HIF2α) antagonists are effective against clear cell renal cell carcinomas (ccRCCs) that highly express HIF2α. To identify potential drug targets in HIF2αlow/− ccRCC, we constructed an epigenetic-focused single-guide RNA library and performed an in vivo CRISPR-Cas9 knockout screen in BALB/c nude mice transplanted with 786-O (HIF2αhigh) or Caki-2 (HIF2αlow/−) cells. We found that the m6A demethylase fat mass and obesity-associated (FTO) gene was indispensable to the growth of HIF2αlow/− but not HIF2αhigh ccRCC. Activation of FTO in HIF2αlow/− ccRCC was caused by an increased intracellular α-ketoglutarate–to-succinate ratio and stabilized bromodomain-containing protein 9 (BRD9) messenger RNA via m6A demethylation. RNA sequencing and chromatin immunoprecipitation sequencing profiling further revealed that SRY-box transcription factor 17 (SOX17) recruited BRD9 to de novo super enhancers associated with genes that feature prominently in ccRCC pathogenesis, including CCND1, VEGFR2, CDC20, SRC, and MAPK6. BRD9 knockdown or the BRD9-selective antagonist I-BRD9 suppressed the growth of HIF2αlow/− but not HIF2αhigh ccRCC cells in vitro. In BALB/c nude mice bearing HIF2αlow/− ccRCC cell line–derived xenografts and patient-derived tumor xenografts, I-BRD9 administration effectively inhibited tumor growth and prolonged the survival of tumor-bearing mice with greater efficacy than sunitinib. Together, these findings indicate that BRD9 is a druggable target for treating HIF2αlow/− ccRCC." @default.
• W3204451293 created "2021-10-11" @default.
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• W3204451293 date "2021-09-29" @default.
• W3204451293 modified "2023-10-12" @default.
• W3204451293 title "Aberrant activation of m6A demethylase FTO renders HIF2α ^low/− clear cell renal cell carcinoma sensitive to BRD9 inhibitors" @default.
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• W3204451293 doi "https://doi.org/10.1126/scitranslmed.abf6045" @default.
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• W3204451293 hasPublicationYear "2021" @default.
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