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Theranostics 2022; 12(14):6363-6379. doi:10.7150/thno.74600 This issue Cite

Research Paper

The N⁶-methyladenosine-mediated lncRNA WEE2-AS1 promotes glioblastoma progression by stabilizing RPN2

Boyan Li^1,2#, Rongrong Zhao^1,2#, Wei Qiu^1,2, Ziwen Pan^1,2, Shulin Zhao^1,2, Yanhua Qi^1,2, Jiawei Qiu^1,2, Shouji Zhang^1,2, Qindong Guo^1,2, Yang Fan^1,2, Hao Xu^1,2, Ming Li^1,2, Gang Li^1,2✉, Hao Xue^1,2✉

1. Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan 250012, Shandong, China.
2. Shandong Key Laboratory of Brain Function Remodeling, Jinan 250012, Shandong, China.
#Boyan Li, Rongrong Zhao contributed equally to this work.

✉ Corresponding authors: Gang Li, Department of Neurosurgery, Qilu Hospital of Shandong University, 107 Wenhua Western Road; Jinan, Shandong 250012, China, E-mail: dr.ligangedu.cn; Tel: 086-0531-82166615. Hao Xue, Department of Neurosurgery, Qilu Hospital of Shandong University, 107 Wenhua Western Road; Jinan, Shandong 250012, China, E-mail: xuehaoedu.cn; Tel: 086-0531-82166615 More

Abstract

Background: Glioblastoma (GBM) is the most common primary brain malignancy and has high aggressiveness and a poor prognosis. N6-methyladenosine (m6A) represents the most prevalent methylation modification of lncRNAs and has been shown to play important roles in the pathophysiological processes of tumors. However, the distribution and function of m6A modifications in lncRNAs in GBM tissues have not been fully revealed.

Methods: The global depiction of m6A-modified lncRNA expression patterns in GBM tumor tissues was screened via m6A high-throughput sequencing. Gain- and loss-of-function assays were performed to investigate the role of WEE2-AS1 in GBM. Mass spectrometry and RNA-pulldown, RNA immunoprecipitation (RIP), luciferase reporter and coimmunoprecipitation assays were performed to explore the mechanism of m6A-mediated upregulation of WEE2-AS1 expression and the downstream mechanism promoting the malignant progression of GBM.

Results: Herein, we report the differential expression profile of m6A-modified lncRNAs in human GBM tissues for the first time. WEE2-AS1 was identified as a novel m6A-modified lncRNA that promotes GBM progression and was post-transcriptionally stabilized by IGF2BP3, an m6A reader. Moreover, we confirmed that WEE2-AS1 promoted RPN2 protein stabilization by preventing CUL2-mediated RPN2 K322 ubiquitination, thereby contributing to GBM malignant progression by activating the PI3K-Akt signaling pathway. In translational medicine, we found that blocking WEE2-AS1 expression improved the therapeutic sensitivity of dasatinib, a central nervous system penetrant that is FDA-approved in GBM.

Conclusions: Overall, this work highlights that WEE2-AS1 may serve as a potential prognostic biomarker and therapeutic target in GBM, the knockdown of which significantly improves the efficacy of dasatinib, providing a promising strategy for improving targeted combination therapy for GBM patients.

Keywords: Glioblastoma, N6-methyladenosine, IGF2BP3, RPN2, ubiquitination

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