miR-766-5p Targets Super-Enhancers by Downregulating CBP and BRD4.

Super-enhancers (SE) are clusters of transcription enhancers that drive gene expression. SEs are typically characterized by high levels of acetylation of histone H3 lysine 27 (H3K27ac), which is catalyzed by the histone lysine acetyltransferase CREB binding protein (CBP). Cancer cells frequently acquire tumor-specific SEs at key oncogenes, such as , which induce several hallmarks of cancer. BRD4 is recruited to SEs and consequently functions as an epigenetic reader to promote transcription of SE-marked genes in cancer cells. miRNAs can be potent candidates for nucleic acid therapeutics for cancer. We previously identified as a miRNA that downregulated expression and inhibited cancer cell growth . In this study, we show that directly targets CBP and BRD4. Concurrent suppression of CBP and BRD4 cooperatively downregulated MYC expression in cancer cells but not in normal cells. Chromatin immunoprecipitation analysis revealed that reduced levels of H3K27ac at SEs via CBP suppression. Moreover, suppressed expression of a BRD4-NUT fusion protein that drives NUT midline carcinoma. administration of suppressed tumor growth in two xenograft models. Collectively, these data suggest that targeting SEs using -based therapeutics may serve as an effective strategy for the treatment of MYC-driven cancers. SIGNIFICANCE: This study demonstrates that targets CBP and BRD4, which can mitigate the protumorigenic consequences of SEs and oncogenic fusion proteins.