miR-3140 suppresses tumor cell growth by targeting BRD4 via its coding sequence and downregulates the BRD4-NUT fusion oncoprotein

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.

The Differential DNA Hypermethylation Patterns of microRNA-137 and microRNA-342 Locus in Early Colorectal Lesions and Tumours

“…In addition, an accurate, comprehensive assessment of a possible correlation between demographic, pathological, clinical, lifestyle and symptom-related features was conducted. Tumour suppressive roles of miR-137 and miR-342 and their epigenetic roles in oral cancer and glioblastoma cell lines have been demonstrated previously [56,57,58,59,60]. Although there are very few previous studies to which the role of miR-137 and miR-342 in triggering CRC is referred, their downregulation has been reported in colon and gastric cancers [30,40].…”

MiR-384 inhibits the proliferation of colorectal cancer by targeting AKT3

“…Up to now, the deregulation of miR-384 has only been observed in a few tumor types, suggesting its function as a cancer suppressor gene. For instance, a microarray showed that miR-384 was down-regulated in laryngeal carcinoma [ 25 ]. Another research implies mir-384 might play an important role in metastasis of melanoma by binding to the 3′UTR of HDAC3 [ 26 ].…”

Reading Cancer: Chromatin Readers as Druggable Targets for Cancer Treatment

“…Nowadays, dozens of miRNAs hindering writers, erasers, and readers have been characterized. Indeed, miR-1340 and miR-608 directly suppressed BRD4 by binding to its coding sequence, reducing in vivo tumor growth in a xenograft mouse model of NMC and hepatocellular carcinoma, respectively [62,63]. MiR-124a inhibited PHF19 over-expression and hindered cell growth in human glioma [64], while miR-19a and miR-19b down-regulated the expression of BARD1 in leukemia [65].…”