Abstract
miR-129-2 is frequently downregulated in multiple cancers. However, how it is silenced in cancers remains unclear. Here we investigated the expression profile and potential biological function of miR-129-2 in glioblastoma (GBM), the most common and lethal form of brain tumors in adults. We showed that miR-129-2 is lost in GBM patient specimens and cultured cell lines. miR-129-2 expression could be restored upon treatment with a histone deadetylase inhibitor (trichostatin A) but not a DNA methylation inhibitor (5-Aza-2'-deoxycytidine), and more profound effect was observed with the treatment of these two drugs in combination. Furthermore, forced expression of miR-129-2 repressed the expression of major oncogenic genes such as PDGFRa and Foxp1 in GBMs. Consistently, expression of miR-129-2 significantly inhibits GBM cell proliferation in vitro. These results reveal that miR-129-2 is epigenetically regulated and functions as a tumor suppressor gene in GBMs, suggesting it may serve as a potential therapeutic target for GBM treatment.
Highlights
MicroRNAs are small non-coding RNAs which are present in plants, animals and some viruses
Results miR-129 is silenced in glioblastoma We fist did in silico analysis of the miR-129 expression profile in various tissues
In this study we demonstrated that expression of miR-129-2 is lost in GBMs mainly through histone deacetylation, and DNA methylation may be involved in this epigenetic regulation
Summary
MicroRNAs are small non-coding RNAs which are present in plants, animals and some viruses. The primary microRNAs are transcribed by RNA polymerase II and recognized and cleaved by the DGCR8 (DiGeorge syndrome critical region 8) protein complex to produce the 70-nt pre-microRNAs, which are released from the nucleus into the cytoplasm, where the Dicer complex cleaves the loop region on the pre-microRNA hairpin to create the 18-22 bp double-stranded mature microRNAs (Gregory et al, 2004). Mature microRNAs are incorporated into a RNA-induced silencing complex (RISC) which interacts with mRNAs, leading to mRNA degradation or translation inhibition (Floyd et al, 2014). MicroRNAs are highly conserved across species and involved in many biologic processes. MicroRNA expression is frequently deregulated through multiple mechanisms such as genomic alterations DNA methylation, aberrant transcription, and defective microRNA processing (Calin et al, 2006; Ma et al, 2010). By regulating target genes expression, microRNAs play an important role in cancer initiation, maintenance, and progression (Calin et al, 2006)
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