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.

放射治疗是胶质瘤患者的标准治疗方法之一；然而，其临床疗效受到放射抗性的限制。我们确定了一种由linc-RA1（放射抗性相关的长基因间非编码 RNA 1）介导的这种抗性机制。与放射敏感细胞和非肿瘤组织相比，Linc-RA1在放射抗性神经胶质瘤细胞和神经胶质瘤组织样本中上调。Linc-RA1与较低的总生存期和胶质瘤的晚期临床分期有关。Linc-RA1在体外和体内促进神经胶质瘤的放射抗性。机械上，linc-RA1通过与 H2B 结合并抑制 H2Bub1 与抑制自噬的泛素特异性蛋白酶 44 (USP44) 之间的相互作用，从而稳定了 H2B K120 单泛素化 (H2Bub1) 的水平，从而有助于胶质瘤放射抗性。这些结果表明，linc-RA1介导的自噬是放射抗性的关键机制，是提高神经胶质瘤患者放疗疗效的可行靶点。