title: Lin-28B transactivation is necessary for Myc-mediated let-7 repression and proliferation.
abstract: Direct control of microRNA (miRNA) expression by oncogenic and tumor suppressor networks results in frequent dysregulation of miRNAs in cancer cells and contributes to tumorigenesis. We previously demonstrated that activation of the c-Myc oncogenic transcription factor (Myc) broadly influences miRNA expression and in particular leads to widespread miRNA down-regulation. miRNA transcripts repressed by Myc include several with potent tumor suppressor activity such as miR-15a/16-1, miR-34a, and let-7 family members. In this study, we have investigated mechanisms downstream of Myc that contribute to miRNA repression. Consistent with transcriptional down-regulation, Myc activity results in the decreased abundance of multiple miRNA primary transcripts. Surprisingly, however, primary transcripts encoding several let-7 miRNAs are not reduced in the high Myc state, suggesting a posttranscriptional mechanism of repression. The Lin-28 and Lin-28B RNA binding proteins were recently demonstrated to negatively regulate let-7 biogenesis. We now show that Myc induces Lin-28B expression in multiple human and mouse tumor models. Chromatin immunoprecipitation and reporter assays reveal direct association of Myc with the Lin-28B promoter resulting in transcriptional transactivation. Moreover, we document that activation of Lin-28B is necessary and sufficient for Myc-mediated let-7 repression. Accordingly, Lin-28B loss-of-function significantly impairs Myc-dependent cellular proliferation. These findings highlight an important role for Lin-28B in Myc-driven cellular phenotypes and uncover an orchestration of transcriptional and posttranscriptional mechanisms in Myc-mediated reprogramming of miRNA expression.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Tsung-Cheng
authors.initials: TC
authors.lastname: Chang
authors.forename: Lauren R
authors.initials: LR
authors.lastname: Zeitels
authors.forename: Hun-Way
authors.initials: HW
authors.lastname: Hwang
authors.forename: Raghu R
authors.initials: RR
authors.lastname: Chivukula
authors.forename: Erik A
authors.initials: EA
authors.lastname: Wentzel
authors.forename: Michael
authors.initials: M
authors.lastname: Dews
authors.forename: Jason
authors.initials: J
authors.lastname: Jung
authors.forename: Ping
authors.initials: P
authors.lastname: Gao
authors.forename: Chi V
authors.initials: CV
authors.lastname: Dang
authors.forename: Michael A
authors.initials: MA
authors.lastname: Beer
authors.forename: Andrei
authors.initials: A
authors.lastname: Thomas-Tikhonenko
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Mendell
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics*
chemical_list: C000715187:Lin28A protein, human; C489427:MYC protein, human; D035683:MicroRNAs; D020033:Protein Isoforms; D016271:Proto-Oncogene Proteins c-myc; D016601:RNA-Binding Proteins; C487931:mirnlet7 microRNA, human