title: Myc overexpression brings out unexpected antiapoptotic effects of miR-34a.
abstract: Downregulation of microRNA-34a by Myc is known to be essential for tumorigenesis and improve tumor-cell survival. Conversely, upregulation of miR-34a by p53 is thought to enhance its acetylation and activity and contribute to the pro-apoptotic effects of this tumor suppressor. We sought to determine whether restoration of miR-34a levels in B-lymphoid cells with Myc overexpression would aid therapeutic apoptosis. Unexpectedly, delivery of miR-34a, which doesn't target p53 directly, severely compromised steady-state p53 levels. This effect was preceded and mediated by direct targeting of Myc, which sustained p53 protein levels via the Arf-Hdm2 pathway. As a result, in the presence of Myc, miR-34a inhibited p53-dependent bortezomib-induced apoptosis as efficiently as anti-p53 small interfering RNA. Conversely, inhibition of miR-34a using antisense RNA sensitized lymphoma cells to therapeutic apoptosis. Thus, in tumors with deregulated Myc expression, miR-34a confers drug resistance and could be considered a therapeutic target.
authors.affiliation: Division of Cancer Pathobiology, Department of Pathology & Laboratory Medicine, The Children's Hospital of Philadelphia, PA 19104-4399, USA.
authors.forename: E
authors.initials: E
authors.lastname: Sotillo
authors.forename: T
authors.initials: T
authors.lastname: Laver
authors.forename: H
authors.initials: H
authors.lastname: Mellert
authors.forename: J M
authors.initials: JM
authors.lastname: Schelter
authors.forename: M A
authors.initials: MA
authors.lastname: Cleary
authors.forename: S
authors.initials: S
authors.lastname: McMahon
authors.forename: A
authors.initials: A
authors.lastname: Thomas-Tikhonenko
mesh_terms: D020727:ADP-Ribosylation Factors / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis*; D011719:Pyrazines / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D011719:Pyrazines; D016159:Tumor Suppressor Protein p53; D000069286:Bortezomib; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D020727:ADP-Ribosylation Factors