Downregulation of lncRNA SNHG1 in hypoxia and stem cells is associated with poor disease prognosis in gliomas

Abstract

ABSTRACT Gliomas are brain tumors associated with high morbidity, relapse and lethality despite improvement in therapeutic regimes. The hypoxic tumor microenvironment is a key feature associated with such poor outcomes in gliomas. The Hypoxia Inducible Factor (HIF) family of transcription factors are master regulators of cellular proliferation, high metabolic rates and angiogenesis via aberrant expression of downstream genes. Recent studies have implicated long non-coding RNAs (lncRNAs) as potential prognostic and diagnostic biomarkers. In this study, identification of hypoxia regulated lncRNA with a bioinformatic pipeline consisting of a newly developed tool “GenOx” was utilized for the identification of Hypoxia Response Element (HRE) and Hypoxia Ancillary Sequence (HAS) motifs in the promoter regions of lncRNAs. This was coupled with molecular, functional and interactome-based analyses of these hypoxia-relevant lncRNAs in primary tumors and cell-line models. We report on the identification of novel hypoxia regulated lncRNAs SNHG12, CASC7 and MF12-AS1. A strong association of RNA splicing mechanisms was observed with enriched lncRNAs. Several lncRNAs have emerged as prognostic biomarkers, of which TP53TG1 and SNHG1 were identified as highly relevant lncRNAs in glioma progression and validated in hypoxia cultured cells. Significantly, we determined that SNHG1 expression in tumor (vs. normal) is different from glioma stem cells, GSC (vs. tumors) and in hypoxia (vs. normoxia), positioning downregulation of SNHG1 to be associated with worsened prognosis.