The Long Non-Coding RNA H19 Drives the Proliferation of Diffuse Intrinsic Pontine Glioma with H3K27 Mutation

Abstract

Diffuse intrinsic pontine glioma (DIPG) is an incurable paediatric malignancy. Identifying the molecular drivers of DIPG progression is of the utmost importance. Long non-coding RNAs (lncRNAs) represent a large family of disease- and tissue-specific transcripts, whose functions have not yet been elucidated in DIPG. Herein, we studied 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 (pedHGGs). The expression and sub-cellular location of H19 lncRNA were 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 the up-regulation of oncogenic let-7 target (e.g., SULF2 and OSMR). H19 is the first functionally characterized lncRNA in DIPG and a promising therapeutic candidate for treating this incurable cancer.

Production and Stabilization of Specific Upregulated Long Noncoding RNA HOXD-AS2 in Glioblastomas Are Mediated by TFE3 and miR-661, Respectively

“…H3K27M mutations frequently occur in high-grade gliomas (HGG) in the midline of the brain, including those in the thalamus, brainstem and spinal cord in children and adolescents [ 61 ]. H3K27M mutation was found in 80% of children with diffuse intrinsic pontine glioma (DIPG) [ 62 ]. In recent years, it was found that H3K27ac increased in H3K27M HGG genome, and the enrichment of H3K27ac increased the expression of repeat elements in H3K27M HGG, which provided a theoretical basis for H3K27M HGG epigenetic therapy [ 63 ].…”

A Novel lncRNA Panel Related to Ferroptosis, Tumor Progression, and Microenvironment is a Robust Prognostic Indicator for Glioma Patients

“…Out of the 14 lncRNAs, eight of them were previously reported. H19 was reported to be upregulated in high-grade glioma and facilitated the proliferation of diffuse intrinsic pontine glioma ( Roig-Carles et al, 2021 ). LINC00346 promotes cell migration, proliferation, and apoptosis by targeting ROCK1( Chen et al, 2020 ) and miR-128-3p/SZRD1 axis ( Geng et al, 2020 ) in glioma.…”

LIN28B and Let-7 in Diffuse Midline Glioma: A Review

“…Emerging data are shining light on H19 lncRNA in glioma, which, similarly to LIN28A/B, works by suppressing let-7 to derepress let-7 targets. A recent study showed that in DIPG cells, H19 lncRNA expression is increased [ 61 ]. Meanwhile, let-7a-5 treatment decreases proliferation [ 61 ].…”

“…A recent study showed that in DIPG cells, H19 lncRNA expression is increased [ 61 ]. Meanwhile, let-7a-5 treatment decreases proliferation [ 61 ]. However, H19 decreases let-7a-5 levels via lncRNA:miR complementarity, which increases expression of let-7a-5 targets ( Figure 6 , [ 61 ]).…”

“…Meanwhile, let-7a-5 treatment decreases proliferation [ 61 ]. However, H19 decreases let-7a-5 levels via lncRNA:miR complementarity, which increases expression of let-7a-5 targets ( Figure 6 , [ 61 ]). It was shown that sulfatase 2 ( SULF2 ) and oncostatin M receptor ( OSMR ) expression is increased [ 61 ].…”