title: MicroRNA-34a modulates c-Myc transcriptional complexes to suppress malignancy in human prostate cancer cells.
abstract: MicroRNA-34a (miR-34a), a potent mediator of tumor suppressor p53, has been reported to function as a tumor suppressor and miR-34a was found to be downregulated in prostate cancer tissues. We studied the functional effects of miR-34a on c-Myc transcriptional complexes in PC-3 prostate cancer cells. Transfection of miR-34a into PC-3 cells strongly inhibited in vitro cell proliferation, cell invasion and promoted apoptosis. Transfection of miR-34a into PC-3 cells also significantly inhibited in vivo xenograft tumor growth in nude mice. miR-34a downregulated expression of c-Myc oncogene by targeting its 3' UTR as shown by luciferase reporter assays. miR-34a was found to repress RhoA, a regulator of cell migration and invasion, by suppressing c-Myc-Skp2-Miz1 transcriptional complex that activates RhoA. Overexpression of c-Myc reversed miR-34a suppression of RhoA expression, suggesting that miR-34a inhibits invasion by suppressing RhoA through c-Myc. miR-34a was also found to repress c-Myc-pTEFB transcription elongation complex, indicating one of the mechanisms by which miR-34a has profound effects on cellular function. This is the first report to document that miR-34a suppresses assembly and function of the c-Myc-Skp2-Miz1 complex that activates RhoA and the c-Myc-pTEFB complex that elongates transcription of various genes, suggesting a novel role of miR-34a in the regulation of transcription by c-Myc complex.
authors.affiliation: Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Yamamura
authors.forename: Sharanjot
authors.initials: S
authors.lastname: Saini
authors.forename: Shahana
authors.initials: S
authors.lastname: Majid
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hirata
authors.forename: Koji
authors.initials: K
authors.lastname: Ueno
authors.forename: Guoren
authors.initials: G
authors.lastname: Deng
authors.forename: Rajvir
authors.initials: R
authors.lastname: Dahiya
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D019859:Proto-Oncogene Proteins c-met; D042925:Positive Transcriptional Elongation Factor B; D020742:rhoA GTP-Binding Protein