Abstract
Radiotherapy is one of the standard treatments for glioma patients; however, its clinical efficacy is limited by radioresistance. We identified a mechanism of such resistance mediated by linc-RA1 (radioresistance-associated long intergenic noncoding RNA 1). Linc-RA1 was upregulated in radioresistant glioma cells and glioma tissue samples, compared with radiosensitive cells and nontumor tissues. Linc-RA1 was associated with inferior overall survival and advanced clinical stage of glioma. Linc-RA1 promoted glioma radioresistance in vitro and in vivo. Mechanistically, linc-RA1 stabilized the level of H2B K120 monoubiquitination (H2Bub1) by combining with H2B and inhibiting the interaction between H2Bub1 and ubiquitin-specific protease 44 (USP44), which inhibited autophagy, thus contributing to glioma radioresistance. These results reveal that linc-RA1-mediated autophagy is a key mechanism of radioresistance and is an actionable target for improving radiotherapy efficacy in patients with glioma.
Highlights
Gliomas are the most common primary brain tumors and are classified as grades I–IV under the World Health Organization (WHO) grading system[1]
Long noncoding RNAs are noncoding transcripts containing more than 200 nucleotides that can control the expression of a gene at the transcriptional, post-transcriptional, or epigenetic levels[5]
Linc-RA1 is upregulated in glioma radioresistant cell lines and correlates with advanced glioma grades and poor prognosis To identify Long noncoding RNAs (lncRNAs) involved in radioresistance of glioma, the expression profile of lncRNAs between the M059J and M059K cells was assessed using microarray analysis in our previous study[16]
Summary
Gliomas are the most common primary brain tumors and are classified as grades I–IV under the World Health Organization (WHO) grading system[1]. High-grade glioma (HGG), including WHO grades III and IV, is the most fatal brain tumor in adults, and its treatment has been largely unsatisfactory[2]. Radiotherapy is one of the limited treatment options with verified clinical efficacy for patients with HGG3. The efficacy of radiotherapy for HGG patients is at best modest, due to radioresistance of the tumor, the underlying mechanisms of which remain poorly characterized[4]. Dysregulated lncRNAs, including lncRNA HULC and CAMTA1, can be closely linked to key aspects of pathology, progression, and outcomes in liver cancer[7,8]. Specific lncRNAs, including lncRNA PCAT-1 and MALAT1, are critically involved in the development and drug resistance in gastric cancer[9,10].
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