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

Cancer Res. 2021 Oct 15;81(20):5190-5201. doi: 10.1158/0008-5472.CAN-21-0649. Epub 2021 Aug 5.

Abstract

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 MYC, 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 miR-766-5p as a miRNA that downregulated MYC expression and inhibited cancer cell growth in vitro. In this study, we show that miR-766-5p 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 miR-766-5p reduced levels of H3K27ac at MYC SEs via CBP suppression. Moreover, miR-766-5p suppressed expression of a BRD4-NUT fusion protein that drives NUT midline carcinoma. In vivo administration of miR-766-5p suppressed tumor growth in two xenograft models. Collectively, these data suggest that targeting SEs using miR-766-5p-based therapeutics may serve as an effective strategy for the treatment of MYC-driven cancers. SIGNIFICANCE: This study demonstrates that miR-766-5p targets CBP and BRD4, which can mitigate the protumorigenic consequences of SEs and oncogenic fusion proteins.