The long non-coding RNA H19 drives the proliferation of diffuse intrinsic pontine glioma with H3K27 mutation

Abstract

ABSTRACTDiffuse intrinsic pontine glioma (DIPG) is an incurable paediatric malignancy. Identifying molecular drivers of DIPG progression is of utmost importance. Long non-coding RNAs (lncRNAs) represent a large family of disease- and tissue-specific transcripts, whose functions have not been yet elucidated in DIPG. Here, we study the oncogenic role of the development-associated H19 lncRNA in DIPG. Bioinformatic analyses of clinical datasets were used to measure the expression of H19 lncRNA in paediatric high-grade gliomas (pedHGG). Expression and sub-cellular location of H19 lncRNA was validated in DIPG cell lines. Locked nucleic acid antisense oligonucleotides were designed to test the function of H19 in DIPG cells. We found that H19 expression was higher in DIPG vs normal brain tissue and other pedHGGs. H19 knockdown resulted in decreased cell proliferation and survival in DIPG cells. Mechanistically, H19 buffers let-7 microRNAs, resulting in up-regulation of oncogenic let-7 target (e.g SULF2, OSMR). H19 is the first functionally characterized lncRNA in DIPG and a promising therapeutic candidate to treat this incurable cancer.