Genetic and epigenetic loss of microRNA-31 leads to feed-forward expression of EZH2 in melanoma

Irfan A. Asangani, Paul W. Harms, Lois Dodson, Mithil Pandhi, Lakshmi P. Kunju, Christopher Maher, Douglas R. Fullen, Timothy M. Johnson, Thomas J. Giordano, Nallasivam Palanisamy, Arul M. Chinnaiyan

Research output: Contribution to journalArticle

98 Scopus citations

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.

Original languageEnglish
Pages (from-to)1011-1025
Number of pages15
JournalOncotarget
Volume3
Issue number9
DOIs
StatePublished - Sep 2012

Keywords

  • DZNep
  • EZH2
  • Melanoma
  • MicroRNA-31
  • Tumor suppressor

Fingerprint Dive into the research topics of 'Genetic and epigenetic loss of microRNA-31 leads to feed-forward expression of EZH2 in melanoma'. Together they form a unique fingerprint.

  • Cite this

    Asangani, I. A., Harms, P. W., Dodson, L., Pandhi, M., Kunju, L. P., Maher, C., Fullen, D. R., Johnson, T. M., Giordano, T. J., Palanisamy, N., & Chinnaiyan, A. M. (2012). Genetic and epigenetic loss of microRNA-31 leads to feed-forward expression of EZH2 in melanoma. Oncotarget, 3(9), 1011-1025. https://doi.org/10.18632/oncotarget.622