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.
Authors	Zhendong Shi, Junxia Zhang, Xiaomin Qian, Lei Han, Kailiang Zhang, Luyue Chen, Jilong Liu, Yu Ren, Ming Yang, Anling Zhang, Peiyu Pu, Chunsheng Kang
Journal	Cancer research (Cancer Res) Vol. 73 Issue 17 Pg. 5519-31 (Sep 01 2013) ISSN: 1538-7445 [Electronic] United States
PMID	23811941 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	AC1MMYR2 compound Antineoplastic Agents MIRN21 microRNA, human MicroRNAs Pyrimidines RNA, Messenger Small Molecule Libraries DICER1 protein, human Ribonuclease III DEAD-box RNA Helicases
Topics	Animals Antineoplastic Agents (pharmacology) Apoptosis (drug effects) Blotting, Western Breast Neoplasms (drug therapy, genetics, pathology) Cell Movement Cell Proliferation (drug effects) DEAD-box RNA Helicases (antagonists & inhibitors, genetics) Disease Progression Epithelial-Mesenchymal Transition Female Fluorescent Antibody Technique Gene Expression Regulation, Neoplastic (drug effects) Glioblastoma (drug therapy, genetics, pathology) Humans Immunoenzyme Techniques In Situ Hybridization, Fluorescence Mice Mice, Inbred BALB C Mice, Nude MicroRNAs (genetics) Models, Molecular Neoplasm Invasiveness Pyrimidines (pharmacology) RNA, Messenger (genetics) Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Ribonuclease III (antagonists & inhibitors, genetics) Small Molecule Libraries Stomach Neoplasms (drug therapy, genetics, pathology) Tumor Cells, Cultured

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