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 HIF2α^low/− 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 (HIF2α^high) or Caki-2 (HIF2α^low/−) cells. We found that the m6A demethylase fat mass and obesity-associated (FTO) gene was indispensable to the growth of HIF2α^low/− but not HIF2α^high ccRCC. Activation of FTO in HIF2α^low/− 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 HIF2α^low/− but not HIF2α^high ccRCC cells in vitro. In BALB/c nude mice bearing HIF2α^low/− 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 HIF2α^low/− ccRCC.

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