title: Genetic and epigenetic loss of microRNA-31 leads to feed-forward expression of EZH2 in melanoma.
abstract: MicroRNAs (miRs) play a key role in cancer etiology by coordinately repressing numerous target genes involved in cell proliferation, migration and invasion. The genomic region in chromosome 9p21 that encompasses miR-31 is frequently deleted in solid cancers including melanoma; however the expression and functional role of miR-31 has not been previously studied in melanoma. Here, we queried the expression status and performed functional characterization of miR-31 in melanoma tissues and cell lines. We found that down-regulation of miR-31 was a common event in melanoma tumors and cell lines and was associated with genomic loss in a subset of samples. Down-regulation of miR-31 gene expression was also a result of epigenetic silencing by DNA methylation, and via EZH2-mediated histone methylation. Ectopic overexpression of miR-31 in various melanoma cell lines inhibited cell migration and invasion. miR-31 targets include oncogenic kinases such as SRC, MET, NIK (MAP3K14) and the melanoma specific oncogene RAB27a. Furthermore, miR-31 overexpression resulted in down-regulation of EZH2 and a de-repression of its target gene rap1GAP; increased expression of EZH2 was associated with melanoma progression and overall patient survival. Taken together, our study supports a tumor suppressor role for miR-31 in melanoma and identifies novel therapeutic targets.
authors.affiliation: Michigan Center for Translational Pathology.
authors.forename: Irfan A
authors.initials: IA
authors.lastname: Asangani
authors.forename: Paul W
authors.initials: PW
authors.lastname: Harms
authors.forename: Lois
authors.initials: L
authors.lastname: Dodson
authors.forename: Mithil
authors.initials: M
authors.lastname: Pandhi
authors.forename: Lakshmi P
authors.initials: LP
authors.lastname: Kunju
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Maher
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Fullen
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Johnson
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Giordano
authors.forename: Nallasivam
authors.initials: N
authors.lastname: Palanisamy
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
mesh_terms: D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D055785:Gene Knockdown Techniques; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: C534612:MIRN31 microRNA, human; D035683:MicroRNAs; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2