The Long Non-coding RNA HIF1A-AS2 Facilitates the Maintenance of Mesenchymal Glioblastoma Stem-like Cells in Hypoxic Niches

• Published in: Cell reports (Cambridge) Vol. 15; no. 11; pp. 2500 - 2509
• Main Authors: Mineo, Marco, Ricklefs, Franz, Rooj, Arun K., Lyons, Shawn M., Ivanov, Pavel, Ansari, Khairul I., Nakano, Ichiro, Chiocca, E. Antonio, Godlewski, Jakub, Bronisz, Agnieszka
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14-06-2016; Elsevier
• Subjects: Cell Hypoxia - genetics; Cell Line, Tumor; Cell Lineage; Disease Progression; Genetic Heterogeneity; Glioblastoma - genetics; Glioblastoma - pathology; Humans; Mesenchymal Stromal Cells - pathology; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RNA, Neoplasm - metabolism; Stem Cell Niche
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.05.018

Long non-coding RNAs (lncRNAs) have an undefined role in the pathobiology of glioblastoma multiforme (GBM). These tumors are genetically and phenotypically heterogeneous with transcriptome subtype-specific GBM stem-like cells (GSCs) that adapt to the brain tumor microenvironment, including hypoxic niches. We identified hypoxia-inducible factor 1 alpha-antisense RNA 2 (HIF1A-AS2) as a subtype-specific hypoxia-inducible lncRNA, upregulated in mesenchymal GSCs. Its deregulation affects GSC growth, self-renewal, and hypoxia-dependent molecular reprogramming. Among the HIF1A-AS2 interactome, IGF2BP2 and DHX9 were identified as direct partners. This association was needed for maintenance of expression of their target gene, HMGA1. Downregulation of HIF1A-AS2 led to delayed growth of mesenchymal GSC tumors, survival benefits, and impaired expression of HMGA1 in vivo. Our data demonstrate that HIF1A-AS2 contributes to GSCs’ speciation and adaptation to hypoxia within the tumor microenvironment, acting directly through its interactome and targets and indirectly by modulating responses to hypoxic stress depending on the subtype-specific genetic context.
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•lncRNA signatures reveal tissue and cellular heterogeneity in defined GBM subtypes•HIF1A-AS2 targets pathways that drive the adaptation to the hypoxic niche in GBM•HIF1A-AS2 is a mesenchymal GSC-specific lncRNA that promotes tumorigenicity
Mineo et al. show that lncRNA HIF1A-AS2 is selectively upregulated in mesenchymal glioblastoma stem-like cells in response to low oxygen. Cellular and molecular rearrangements driven by HIF1A-AS2 and proteins from direct interactome indicate that this lncRNA acts in a tumor anatomic site-dependent fashion to control adaptation to hypoxic stress.