title: Regulation of several androgen-induced genes through the repression of the miR-99a/let-7c/miR-125b-2 miRNA cluster in prostate cancer cells.
abstract: The androgen receptor (AR) stimulates and represses gene expression to promote the initiation and progression of prostate cancer. Here, we report that androgen represses the miR-99a/let7c/125b-2 cluster through AR and anti-androgen drugs block the androgen-repression of the miRNA cluster. AR directly binds to the host gene of the miR-99a/let7c/125b-2 cluster, LINC00478. Expression of the cluster is repressed or activated by chromatin remodelers EZH2 or JMJD3 in the presence or absence of androgen, respectively. Bioinformatics analysis reveals a significant enrichment of targets of miR-99a, let-7c and miR-125b in androgen-induced gene sets, suggesting that downregulation of the miR-99a/let7c/125b-2 cluster by androgen protects many of their target mRNAs from degradation and indirectly assists in the gene induction. We validated the hypothesis with 12 potential targets of the miR-99a/let7c/125b-2 cluster induced by androgen: 9 out of the 12 mRNAs are downregulated by the microRNA cluster. To ascertain the biological significance of this hypothesis, we focused on IGF1R, a known prostate cancer growth factor that is induced by androgen and directly targeted by the miR-99a/let7c/125b-2 cluster. The androgen-induced cell proliferation is ameliorated to a similar extent as anti-androgen drugs by preventing the repression of the microRNAs or induction of IGF1R in androgen-dependent prostate cancer cells. Expression of a microRNA-resistant form of IGF1R protects these cells from inhibition by the miR-99a/let7c/125b-2 cluster. These results indicate that a thorough understanding of how androgen stimulates prostate cancer growth requires not only an understanding of genes directly induced/repressed by AR, but also of genes indirectly induced by AR through the repression of key microRNAs.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia Health Sciences Center, Charlottesville, VA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Sun
authors.affiliation: 1] Department of Biochemistry and Molecular Genetics, University of Virginia Health Sciences Center, Charlottesville, VA, USA [2] Department of Computer Science, University of Virginia, Charlottesville, VA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Layer
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia Health Sciences Center, Charlottesville, VA, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Mueller
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia Health Sciences Center, Charlottesville, VA, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Cichewicz
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia Health Sciences Center, Charlottesville, VA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Negishi
authors.affiliation: 1] Department of Biochemistry and Molecular Genetics, University of Virginia Health Sciences Center, Charlottesville, VA, USA [2] Center for Cell Signaling, University of Virginia, Charlottesville, VA, USA.
authors.forename: B M
authors.initials: BM
authors.lastname: Paschal
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia Health Sciences Center, Charlottesville, VA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Dutta
mesh_terms: D000728:Androgens / Q000502:physiology*; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D000728:Androgens; C531888:MIRN125 microRNA, human; C561679:MIRN99 microRNA, human; D035683:MicroRNAs