Genetic and epigenetic loss of microRNA-31 leads to feed-forward expression of EZH2 in melanoma
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Irfan A. Asangani1,2,*,Paul W. Harms1,2,3,*, Lois Dodson1, Mithil Pandhi1, Lakshmi P. Kunju2, Chris A. Maher1,2,4, Douglas R. Fullen2,3, Timothy M. Johnson3, Thomas J. Giordano2, Nallasivam Palanisamy1,2,5,8, Arul M. Chinnaiyan1,2,5,6,7,8
1 Michigan Center for Translational Pathology
2 Department of Pathology, University of Michigan
3 Department of Dermatology, University of Michigan
4 Center for Computational Medicine and Bioinformatics
5 Comprehensive Cancer Center, University of Michigan Medical School
6 Howard Hughes Medical Institute, University of Michigan Medical School
7 Department of Urology, University of Michigan
8 Shared senior authors
* These authors contributed equally to this work
Arul M. Chinnaiyan, email:
Keywords: : microRNA-31, melanoma, tumor suppressor, EZH2, DZNep
Received: August 15, 2012, Accepted: August 28, 2012, Published: August 31, 2012
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.
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