title: A statin-regulated microRNA represses human c-Myc expression and function.
abstract: c-Myc dysregulation is one of the most common abnormalities found in human cancer. MicroRNAs (miRNAs) are functionally intertwined with the c-Myc network as multiple miRNAs are regulated by c-Myc, while others directly suppress c-Myc expression. In this work, we identified miR-33b as a primate-specific negative regulator of c-Myc. The human miR-33b gene is located at 17p11.2, a genomic locus frequently lost in medulloblastomas, of which a subset displays c-Myc overproduction. Through a small-scale screening with drugs approved by the US Food and Drug Administration (FDA), we found that lovastatin upregulated miR-33b expression, reduced cell proliferation and impaired c-Myc expression and function in miR-33b-positive medulloblastoma cells. In addition, a low dose of lovastatin treatment at a level comparable to approved human oral use reduced tumour growth in mice orthotopically xenografted with cells carrying miR-33b, but not with cells lacking miR-33b. This work presents a highly promising therapeutic option, using drug repurposing and a miRNA as a biomarker, against cancers that overexpress c-Myc.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, University of Louisville, KY, USA.
authors.forename: Apana A L
authors.initials: AA
authors.lastname: Takwi
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Lindsey E
authors.initials: LE
authors.lastname: Becker Buscaglia
authors.forename: Jingwen
authors.initials: J
authors.lastname: Zhang
authors.forename: Saibyasachi
authors.initials: S
authors.lastname: Choudhury
authors.forename: Ae Kyung
authors.initials: AK
authors.lastname: Park
authors.forename: Mofang
authors.initials: M
authors.lastname: Liu
authors.forename: Ken H
authors.initials: KH
authors.lastname: Young
authors.forename: Woong-Yang
authors.initials: WY
authors.lastname: Park
authors.forename: Robert C G
authors.initials: RC
authors.lastname: Martin
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001932:Brain Neoplasms / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation; D006801:Humans; D008148:Lovastatin / Q000008:administration & dosage; D008297:Male; D008527:Medulloblastoma / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents; C550416:MIRN33a microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D008148:Lovastatin