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The BET family member BRD4 is a bromodomain-containing protein that plays a vital role in driving oncogene expression. Given their pivotal role in regulating oncogenic networks in various cancer types, BET inhibitors (BETi) have been developed, but the clinical application has been impeded by dose-limiting toxicity and resistance. Understanding the mechanisms of BRD4 activity and identifying predictive biomarkers could facilitate the successful clinical use of BETis. Herein, we show that KDM5C and BRD4 cooperate to sustain tumor cell growth. Mechanistically, KDM5C interacted with BRD4 and stimulated BRD4 enhancer recruitment. Moreover, binding of the BRD4 C-terminus to KDM5C stimulated the H3K4 demethylase activity of KDM5C. The abundance of both KDM5C-associated BRD4 and H3K4me1/3 determined the transcriptional activation of many oncogenes. Notably, depletion or pharmacologic degradation of KDM5C dramatically reduced BRD4 chromatin enrichment and significantly increased BETi efficacy across multiple cancer types in both tumor cell lines and patient-derived organoid models. Furthermore, targeting KDM5C in combination with BETi suppressed tumor growth in vivo in a xenograft mouse model. Collectively, this work reveals a KDM5C-mediated mechanism by which BRD4 regulates transcription, providing a rationale for incorporating BETi into combination therapies with KDM5C inhibitors to enhance treatment efficacy., Significance: BRD4 is recruited to enhancers in a bromodomain-independent manner by binding KDM5C and stimulates KDM5C H3K4 demethylase activity, leading to synergistic effects of BET and KDM5C inhibitor combinations in cancer., (©2024 American Association for Cancer Research.)