The tumor suppressor microRNA, miR-124a, is regulated by epigenetic silencing and by the transcriptional factor, REST in glioblastoma

Amanda Tivnan, Jack Zhao, Terrance Grant Johns, Bryan Day, Brett W Stringer, Andrew W Boyd, Sarita Tiwari, Keith M Giles, Charlie Teo, Kerrie McDonald

Research output: Contribution to journalArticleResearchpeer-review

20 Citations (Scopus)

Abstract

Reduced levels of specific microRNA in cancer are frequently reported and associated with attenuated cancer genes and associated pathways. We previously reported a loss of miR-124a in glioblastoma (GBM) patient specimens; however, the upstream causes of this loss are largely unknown. Loss of miR-124a has been attributed to hypermethylation while other studies have shown miR-124a to be regulated by the repressor-element-1-silencing transcription factor (REST, also known as neuron-restrictive silencing factor). This current study looked at both epigenetic and transcription factor regulation as potential mechanisms resulting in the loss of miR-124a expression in GBM patient specimens and cell lines. Hypermethylation of miR-124a was observed in 82 of GBM patient specimens (n = 56). In vitro miR-124a expression levels also increased after treatment of several patient-derived cell lines with 5-aza-2 -deoxycytidine. Additionally, we also demonstrated a positive interaction between REST activity and miR-124a using a luciferase-binding assay and we correlated the reciprocal expression of REST and miR-124a in our clinical cohort. This result indicates that miR-124a expression may also be modulated through the upstream targeting of REST. Preclinical studies involving inhibitors of REST and treatment with demethylating agents with the intent to increase miR-124a levels could be interesting.
Original languageEnglish
Pages (from-to)1459 - 1465
Number of pages7
JournalTumor Biology
Volume35
Issue number2
DOIs
Publication statusPublished - 2014

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