Abstract
Bromodomain Containing 4 (BRD4) mediates transcriptional elongation of the oncogene MYC by binding to acetylated histones. BRD4 has been shown to play a critical role in tumorigenesis in several cancers, and the BRD4-NUT fusion gene is a driver of NUT midline carcinoma (NMC), a rare but highly lethal cancer. microRNAs (miRNAs) are endogenous small non-coding RNAs that suppress target gene expression by binding to complementary mRNA sequences. Here, we show that miR-3140, which was identified as a novel tumor suppressive miRNA by function-based screening of a library containing 1090 miRNA mimics, directly suppressed BRD4 by binding to its coding sequence (CDS). miR-3140 concurrently downregulated BRD3 by bind to its CDS as well as CDK2 and EGFR by binding to their 3’ untranslated regions. miR-3140 inhibited tumor cell growth in vitro in various cancer cell lines, including EGFR tyrosine kinase inhibitor-resistant cells. Interestingly, we found that miR-3140 downregulated the BRD4-NUT fusion protein and suppressed in vitro tumor cell growth in a NMC cell line, Ty-82 cells. Furthermore, administration of miR-3140 suppressed in vivo tumor growth in a xenograft mouse model. Our results suggest that miR-3140 is a candidate for the development of miRNA-based cancer therapeutics.
Highlights
The bromodomain and extra-terminal domain (BET) family proteins, including BRD2, BRD3, Bromodomain Containing 4 (BRD4), and BRDT, contain two conserved bromodomains that are associated with acetylated lysine in histones, facilitating transcriptional activation as epigenetic readers[1,2]
Many studies have revealed that miRNAs repress gene expression by binding to 3′ untranslated regions (3′UTR) of mRNAs, an increasing body of evidence supports that miRNAs bind to the coding sequences (CDS) of target mRNAs and that miRNA binding to the CDS of mRNAs can effectively suppress translation[29,30,31]
We revealed that miR-3140 suppressed the BRD4-NUT oncoprotein in NUT midline carcinoma (NMC) cells and that miR-3140 inhibited in vitro tumor cell growth in NMC cells
Summary
The bromodomain and extra-terminal domain (BET) family proteins, including BRD2, BRD3, BRD4, and BRDT, contain two conserved bromodomains that are associated with acetylated lysine in histones, facilitating transcriptional activation as epigenetic readers[1,2]. The translocation breakpoints occur within intron 10 of the BRD4 gene (19p13.1) and intron 2 of NUT (15q14), such that the BRD4-NUT protein contains www.nature.com/scientificreports/. Both acetyl-histone binding bromodomains and the extraterminal domain of BRD4 (i.e., the full functional domain of BRD4)[13]. Several studies have shown that BET bromodomain inhibitors are highly effective against various intractable cancers, including triple negative breast cancer[8], pancreatic cancer[9], and NMC22, resistance to BET bromodomain inhibition can be acquired through various mechanisms[8,23]. Our previous study revealed that miR-432–3p directly targets KEAP1 via its CDS32
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