Genome-wide pharmacologic unmasking identifies tumor suppressive microRNAs in multiple myeloma

Chonglei Bi, Tae Hoon Chung, Gaofeng Huang, Jianbiao Zhou, Junli Yan, Gregory J. Ahmann, Rafael Fonseca, Wee Joo Chng

Research output: Contribution to journalArticle

33 Scopus citations

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 genomewide 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.

Original languageEnglish (US)
Pages (from-to)26508-26518
Number of pages11
JournalOncotarget
Volume6
Issue number28
DOIs
StatePublished - Jan 1 2015

Keywords

  • Epigenetics/MicroRNA
  • Myeloma
  • Tumor suppressor

ASJC Scopus subject areas

  • Oncology

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    Bi, C., Chung, T. H., Huang, G., Zhou, J., Yan, J., Ahmann, G. J., Fonseca, R., & Chng, W. J. (2015). Genome-wide pharmacologic unmasking identifies tumor suppressive microRNAs in multiple myeloma. Oncotarget, 6(28), 26508-26518. https://doi.org/10.18632/oncotarget.4769