Abstract
Abstract Bromodomain and extra-terminal domain (BET) proteins have emerged as promising therapeutic targets in glioblastoma and many other cancers. Small molecule mimics of acetylated histones inhibit BET protein function and reduce expression of several oncogenes required for glioblastoma (GBM) progression. However, the mechanism through which BET protein inhibition reduces GBM growth is not completely understood. Long noncoding RNAs (lncRNAs) are important epigenetic regulators with critical roles in cancer initiation and malignant progression but mechanistic insight into their expression and regulation by bromodomain inhibitors remains elusive. In this study we utilized single molecule sequencing (SMS) to comprehensively profile lncRNAs differentially expressed in GBM and we identified a subset of GBM-specific lncRNAs whose expression is regulated by BET proteins. Treatment of GBM cells with the BET protein inhibitor I-BET151 reduced levels of the tumor-promoting lncRNA HOTAIR and restored the expression of several other GBM-down-regulated lncRNAs. Conversely, overexpression of HOTAIR in conjunction with I-BET treatment rescues the antiproliferative activity of I-BET151. Moreover, chromatin immunoprecipitation analysis demonstrated binding of Brd4 to the HOTAIR promoter suggesting that BET proteins can directly regulate lncRNA expression. Our data unravel a previously unappreciated mechanism through which BET proteins control tumor growth of glioblastoma cells and suggest that lncRNA networks may, in part, mediate the anti-proliferative effects of many epigenetic inhibitors currently in clinical trials for cancer and other diseases. Note: This abstract was not presented at the meeting. Citation Format: Chiara Pastori, Philip Kapranov, Clara Penas, Georges St.Laurent,Nagi Ayad, Claes Wahlestedt. The Bromodomain inhibitors regulate long noncoding RNAs controlling glioblastoma progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4764. doi:10.1158/1538-7445.AM2015-4764
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