BRD4 controls Long noncoding RNAs to regulate glioblastoma proliferation

Long non-coding RNAs (lncRNA) are non-protein coding transcripts longer than 200 nucleotides. They have been looked as rubbish of the transcripts before, however, recently study indicate that they play critical roles in cancer initiation and malignant progression. FDA has approved five epigenetic drugs for use in cancer treatment: two DNA methyltransferase (DNMT) inhibitors and three histone deacetylase (HDAC) inhibitors. BET bromodomain inhibitors exert a broad spectrum of desirable biological effects such as anticancer and anti-inflammatory properties.

BRD4 controls Long noncoding RNAs to regulate glioblastoma proliferation

Firstly, we profile lncRNAs differentially expressed in GBM. We have analyzed the RNA sequencing data by testing expression of each annotated transcript in each individual GBM sample compared against all normal samples.

Next, knockdown of HOTAIR causes apoptosis and reduces the proliferation of glioblastoma cells in vitro and in vivo.

Finally, Treatment of GBM cells with the BET bromdomain inhibitor I-BET151 reduced levels of the tumor-promoting lncRNA HOX transcript antisense RNA (HOTAIR) and restored the expression of several other GBM down-regulated lncRNAs. BRD4 bind to the HOTAIR promoter, suggesting that BET proteins can directly regulate lncRNA expression.

To summary, we have identified a mechanism that small molecule inhibitors of BET bromodomain proteins reduce expression of several oncogenes required for GBM progression.

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