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Linc-RA1 通过抑制 H2Bub1/USP44 复合物的形成来抑制自噬并促进胶质瘤细胞的放射抵抗。

Linc-RA1 inhibits autophagy and promotes radioresistance by preventing H2Bub1/USP44 combination in glioma cells.

机构信息

Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, People's Republic of China.

Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, People's Republic of China.

出版信息

Cell Death Dis. 2020 Sep 15;11(9):758. doi: 10.1038/s41419-020-02977-x.

DOI:10.1038/s41419-020-02977-x
PMID:32934196
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7492255/
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.

摘要

放射疗法是胶质母细胞瘤患者的标准治疗方法之一；然而，其临床疗效受到放射抵抗的限制。我们发现了一种由 linc-RA1（放射抵抗相关长基因间非编码 RNA 1）介导的这种抵抗的机制。与放射敏感细胞和非肿瘤组织相比，linc-RA1 在放射抵抗的胶质母细胞瘤细胞和组织样本中上调。linc-RA1 与胶质母细胞瘤患者的总生存期较差和临床分期较晚相关。linc-RA1 在体外和体内促进胶质母细胞瘤的放射抵抗。从机制上讲，linc-RA1 通过与 H2B 结合并抑制 H2Bub1 与泛素特异性蛋白酶 44（USP44）之间的相互作用来稳定 H2B K120 单泛素化（H2Bub1）的水平，从而抑制自噬，从而有助于胶质母细胞瘤的放射抵抗。这些结果表明，linc-RA1 介导的自噬是放射抵抗的关键机制，是提高胶质母细胞瘤患者放射治疗效果的可行靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e783/7492255/f20651a4ddb1/41419_2020_2977_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e783/7492255/f555345c158e/41419_2020_2977_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e783/7492255/32d9c8fa24aa/41419_2020_2977_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e783/7492255/d3cccfcdf45a/41419_2020_2977_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e783/7492255/7191748a7f10/41419_2020_2977_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e783/7492255/8a52343b25fc/41419_2020_2977_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e783/7492255/b3ceabbaee85/41419_2020_2977_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e783/7492255/f20651a4ddb1/41419_2020_2977_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e783/7492255/f555345c158e/41419_2020_2977_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e783/7492255/32d9c8fa24aa/41419_2020_2977_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e783/7492255/d3cccfcdf45a/41419_2020_2977_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e783/7492255/7191748a7f10/41419_2020_2977_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e783/7492255/8a52343b25fc/41419_2020_2977_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e783/7492255/b3ceabbaee85/41419_2020_2977_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e783/7492255/f20651a4ddb1/41419_2020_2977_Fig7_HTML.jpg

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