title: Genome-wide pharmacologic unmasking identifies tumor suppressive microRNAs in multiple myeloma.
abstract: Epigenetic alterations have emerged as an important cause of microRNA (miRNA) deregulation. In Multiple Myeloma (MM), a few tumor suppressive miRNAs silenced by DNA hypermethylation have been reported, but so far there are few systemic investigations on epigenetically silenced miRNAs. We conducted genome-wide screening for tumor suppressive miRNAs epigenetically silenced in MM. Four Human MM Cell lines were treated with demethylating agent 5'azacytidine (5'aza). Consistently upregulated miRNAs include miR-155, miR-198, miR-135a*, miR-200c, miR-125a-3p, miR-188-5p, miR-483-5p, miR-663, and miR-630. Methylation array analysis revealed increased methylation at or near miRNA-associated CpG islands in MM patients. Ectopic restoration of miR-155, miR-198, miR-135a*, miR-200c, miR-663 and miR-483-5p significantly repressed MM cell proliferation, migration and colony formation. Furthermore, we derived a 33-gene signature from predicted miRNA target genes that were also upregulated in MM patients and associated with patient survival in three independent myeloma datasets. In summary, we have revealed important, epigenetically silenced tumor suppressive miRNAs by pharmacologic reversal of epigenetic silencing.
authors.affiliation: Experimental Therapeutics, Cancer Science Institute of Singapore, Singapore.|Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Chonglei
authors.initials: C
authors.lastname: Bi
authors.affiliation: Experimental Therapeutics, Cancer Science Institute of Singapore, Singapore.
authors.forename: Tae-Hoon
authors.initials: TH
authors.lastname: Chung
authors.affiliation: Experimental Therapeutics, Cancer Science Institute of Singapore, Singapore.
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Huang
authors.affiliation: Experimental Therapeutics, Cancer Science Institute of Singapore, Singapore.
authors.forename: Jianbiao
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Experimental Therapeutics, Cancer Science Institute of Singapore, Singapore.
authors.forename: Junli
authors.initials: J
authors.lastname: Yan
authors.affiliation: Mayo Clinic, Scottsdale, Arizona, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Ahmann
authors.affiliation: Mayo Clinic, Scottsdale, Arizona, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Fonseca
authors.affiliation: Experimental Therapeutics, Cancer Science Institute of Singapore, Singapore.|Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Department of Hematology-Oncology, National University Cancer Institute, National University Health System, Singapore.
authors.forename: Wee Joo
authors.initials: WJ
authors.lastname: Chng
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019295:Computational Biology; D019175:DNA Methylation / Q000187:drug effects*; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing / Q000187:drug effects*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D016016:Proportional Hazards Models
chemical_list: D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D035683:MicroRNAs; D015254:DNA Modification Methylases
keywords: epigenetics; microRNA; myeloma; tumor suppressor