AC1MMYR2, an Inhibitor of Dicer-Mediated Biogenesis of Oncomir miR-21, Reverses Epithelial–Mesenchymal Transition and Suppresses Tumor Growth and Progression

Abstract

The extensive involvement of miRNAs in cancer pathobiology has opened avenues for drug development based on oncomir inhibition. Dicer is the core enzyme in miRNA processing that cleaves the terminal loop of precursor microRNAs (pre-miRNAs) to generate mature miRNA duplexes. Using the three-dimensional structure of the Dicer binding site on the pre-miR-21 oncomir, we conducted an in silico high-throughput screen for small molecules that block miR-21 maturation. By this method, we identified a specific small-molecule inhibitor of miR-21, termed AC1MMYR2, which blocked the ability of Dicer to process pre-miR-21 to mature miR-21. AC1MMYR2 upregulated expression of PTEN, PDCD4, and RECK and reversed epithelial-mesenchymal transition via the induction of E-cadherin expression and the downregulation of mesenchymal markers, thereby suppressing proliferation, survival, and invasion in glioblastoma, breast cancer, and gastric cancer cells. As a single agent in vivo, AC1MMYR2 repressed tumor growth, invasiveness, and metastasis, increasing overall host survival with no observable tissue cytotoxicity in orthotopic models. Our results offer a novel, high-throughput method to screen for small-molecule inhibitors of miRNA maturation, presenting AC1MMYR2 as a broadly useful candidate antitumor drug.

A Graphene-enhanced imaging of microRNA with enzyme-free signal amplification of catalyzed hairpin assembly in living cells

“…The results indicated that the level of miR-21 obtained via CHA-based assay were in consistent with the RT-PCR results of miR-21 expression between MCF-7 and MCF-10A cells. AC1MMYR2, an inhibitor of miR-21, which blocked the generate process of pre-miR-21 to mature miR-21 in glioblastoma, breast cancer, and gastric cancer cells (Ren et al, 2015;Shi et al, 2013). miR-21 expression was tested using CHA-based assay in MCF-7, MCF-10A, MDA-MB-231, HeLa and MDA-MB-435 by AC1MMYR2 (Figs.…”

MiR-1271 Inhibits Cell Proliferation, Invasion and EMT in Gastric Cancer by Targeting FOXQ1

“…Accumulating evidence indicates that abnormal miRNAs can function as oncogenes or tumor suppressors in the initiation and progression of human cancers, including GC [16,17,18]. For instance, miR-21 has been found to be overexpressed in GC and to promote tumor proliferation and invasion by negatively regulating important tumor suppressor genes such as PTEN, PDCD4, and RECK [19,20,21]. By contrast, overexpression of miR-141 could suppress GC cell invasion by directly repressing STAT4 [22].…”

Targeting strategies on miRNA-21 and PDCD4 for glioblastoma

“…[5][6][7] The discovery of miRNAs in cancer pathobiology will open up another novel avenue for drug development based on inhibition of onco-miRNAs. 8 Programmed cell death 4 (PDCD4) was first identified as a protein upregulated during apoptosis and suppressed tumorigenesis. 9,10 As a target transcript encoding a protein involved in tumor suppression, the decreased expression of PDCD4 in glioblastoma-derived cell lines thus suggests that it is a tumor-suppressor gene.…”

“…118Dicer is the core enzyme in miRNA processing that cleaves the terminal loop of precursor miRNAs to generate mature miRNA duplexes. AC1MMYR2 can block the ability of Dicer () to process pre-miR-21 to mature miR-21 119. Additionally, AC1MMYR2 upregulates expression of PTEN, PDCD4, RECK and reverses epithelial-mesenchymal transition via the induction of E-cadherin expression and the downregulation of mesenchymal markers, thereby suppressing proliferation, survival, and invasion in glioblastoma, breast cancer, and gastric cancer cells.…”