Abstract LB-114: The long noncoding RNA HOTAIR promotes glioblastoma cell proliferation

Abstract

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain malignancy in adults. The standard treatment consists of surgery followed by radiotherapy and chemotherapy, although this only modestly affects patient survival. Partial tumor resection and poor drug delivery to the brain impede effective treatment options. The development of high-throughput sequencing technology has allowed the cancer research community to identify hundreds of genetic alterations such as amplification, deletion, mutation, and changes in gene expression. However, all this information still needs to be translated into new therapeutic approaches. These novel therapies may come from understanding long non-coding RNAs (lncRNAs). lncRNAs modulate transcription, regulate post-transcriptional RNA processing, translation, DNA methylation, and chromatin architecture through local (cis) and long distance (trans) mechanisms. Although relatively few lncRNAs have been functionally characterized, fewer are reported to have oncogenic or tumor suppressor properties. Recently, small signatures of 6 long-noncoding RNAs with altered expression have been reported for glioblastoma and these lncRNAs have shown correlation to overall survival. Using the Helicos Next Generation Sequencing platform 12 GBM samples and 8 controls were sequenced. Our lab identified hundreds of lncRNAs potentially dysregulated in GBM. Among these there was the well-known lncRNA HOTAIR, which was found to be massively upregulated in GBM. This observation correlated with what has been observed in other cancers. However, increased expression of HOTAIR has been linked to poor prognosis due to metastatic events. Here we show that in glioblastoma HOTAIR does not promote metastasis, but instead sustains the ability of these cells to proliferate. We demonstrate that HOTAIR knockdown in GBM strongly impairs the proliferation of cells and induces apoptosis in vitro and in vivo experiments. To identify the direct gene targets of HOTAIR we employed the chirp technique (chromatin isolation by RNA precipitation), which allowed us to explain how this lncRNA affects gene transcription involved in proliferation/apoptosis and shed light on the cellular pathways regulated by HOTAIR. In addition to cell cycle regulation mediated by HOTAIR we find that certain epigenetic enzyme inhibitors potently downregulate HOTAIR expression. These exciting studies define a novel mechanism through which these enzymes control cell proliferation via lncRNA expression. Citation Format: Chiara Pastori, Clara Penas, Philipp Kapranov, Georges St.Laurent, Ming Zhang, Nagi Ayad, Claes Wahlestedt. The long noncoding RNA HOTAIR promotes glioblastoma cell proliferation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-114. doi:10.1158/1538-7445.AM2014-LB-114