Abstract 3541: HOTAIR modulates β-catenin signaling pathway through NLK and NFAT5 in human glioblastoma

Abstract

Abstract Background Glioblastoma (GBM) is the most common malignant tumor of human central nervures system with poor prognosis. A new class of transcripts, long noncoding RNAs (lncRNAs), has been recently found to be pervasively transcribed in the genome. Recent progress suggests that the involvement of lncRNAs in human cancers could be far more prevalent than previously appreciated. HOTAIR, lncRNA Hox transcript antisense intergenic RNA, has been characterized as a novel hall marker to predict poor prognosis in glioma. HOTAIR serves as a modular scaffold by interacting with the polycomb repressive complex 2 (PRC2) and the lysine-specific demethylase 1 (LSD1) corepressor for element-1-silencing transcription factor (CoREST) complex to silence the HOXD loci in trans. Constitutive activation of the Wnt/β-catenin pathway is a common feature of human cancers and contributes to its development, progression and metastasis. Methods RNA sequencing and qPCR were used to determine HOTAIR expression status in GBM samples. TOP/FOP flash luciferase assays and western blot were employed to identify the effect of HOTAIR's function on the Wnt/β-catenin pathway activity. In addition, FCM, transwell assay, clone formation assay were used to examine HOTAIR's biological function in regulating GBM cell phenotype. Results We show β-catenin pathway is associated to HOTAIR expression by RNA sequencing in GBM cell lines and large scale glioma samples. Besides, increasing NLK and NFAT5 expression, PKM2 and β-catenin pathway inhibition is induced by HOTAIR knockdown in vivo and in vitro. Moreover, HOTAIR knockdown can partially overcome hypoxia stimulation to U87 and U87VIII cells, block cell cycle at G1 phase, and attenuate GBM cell invasion or EMT like transformation. And EZH2 domain may contribute to HOTAIR's biological function. Conclusion Our data indicate that HOTAIR expression is correlated with the overexpression ofβ-catenin pathway activation in both GBM cell lines and tissues. And HOTAIR can serve as a therapeutic target in gliobalstoma, relating its oncogenic effects to activation of β-catenin pathway. Citation Format: Xuan Zhou, Yu Ren, Lei Han, Chunsheng Kang. HOTAIR modulates β-catenin signaling pathway through NLK and NFAT5 in human glioblastoma. [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 3541. doi:10.1158/1538-7445.AM2014-3541