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

David Roig-Carles,Rebecca L Mather,Ella Waters,Alan Mackay,Katie F Loveson,Chris Jones,Francesco Crea,Helen L Fillmore,Ilaria Alborelli,Jon Golding,Holly Jackson,Massimiliano Manzo

doi:10.3390/ijms22179165

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.

Highlights

Malignant brain tumours are a leading cause of death in paediatric patients
To confirm the expression of H19 Long non-coding RNAs (lncRNAs) in Diffuse intrinsic pontine glioma (DIPG) tissue, we analysed open-access that H19 levels are significantly increased in the DIPG tissue of the “Allis-45-custom-ilmclinical datasets of paediatric high-grade gliomas (pedHGGs) and normal brain tissue
We showed that H19 is up-regulated in DIPGs, and that silencing

Summary

Introduction

Malignant brain tumours are a leading cause of death in paediatric patients. Diffuse intrinsic pontine glioma (DIPG) is a type of paediatric high-grade glioma (pedHGG)originating in the brainstem and affecting children with a median age of six to seven years [1,2]. Malignant brain tumours are a leading cause of death in paediatric patients. Diffuse intrinsic pontine glioma (DIPG) is a type of paediatric high-grade glioma (pedHGG). Originating in the brainstem and affecting children with a median age of six to seven years [1,2]. DIPGs are highly infiltrative and belong to the fibrillary astrocytoma family, where lesions are classified as either WHO grade III or IV [3]. Substitution of lysine at the 27 position of the histone 3 locus with methionine (H3K27M at either H3.1 or H3.3) has been suggested to drive the oncogenesis of DIPGs [4]. H3K27M substitution is identified in approximately 80% of histologically confirmed DIPGs. The

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