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

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.