LINC00921 reduces lung cancer radiosensitivity by destabilizing NUDT21 and driving aberrant MED23 alternative polyadenylation.

Abstract

Alternative polyadenylation (APA) plays a major role in controlling transcriptome diversity and therapeutic resistance of cancers. However, long non-coding RNAs (lncRNAs) involved in pathological APA remain poorly defined. Here, we functionally characterize LINC00921, a MED13L/P300-induced oncogenic lncRNA, and show that it is required for global regulation of APA in non-small cell lung cancer (NSCLC). LINC00921 shows significant potential for reducing NSCLC radiosensitivity, and high LINC00921 levels are associated with a poor prognosis for patients with NSCLC treated with radiotherapy. LINC00921 controls NUDT21 stability by facilitating binding of NUDT21 with the E3 ligase TRIP12. LINC00921-induced destabilization of NUDT21 promotes 3' UTR shortening of MED23 mRNA via APA, which, in turn, leads to elevated MED23 protein levels in cancer cells and nuclear translocation of β-catenin and thereby activates expression of multiple β-catenin/T cell factor (TCF)/lymphoid enhancer-binding factor (LEF)-regulated core oncogenes (c-Myc, CCND1, and BMP4). These findings highlight the importance of functionally annotating lncRNAs controlling APA and suggest the clinical potential of therapeutics for advanced NSCLC.

• Authors: Nasha Zhang, Xijun Liu, Linying Huang, Jiajia Zeng, Chi Ma, Linyu Han, Wenwen Li, Jinming Yu, Ming Yang
• Journal: Cell reports (Cell Rep) Vol. 42 Issue 12 Pg. 113479 (12 26 2023) ISSN: 2211-1247 [Electronic] United States
• PMID: 37999979 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• 3' Untranslated Regions
• beta Catenin
• Carrier Proteins
• Cleavage And Polyadenylation Specificity Factor
• RNA, Long Noncoding
• TRIP12 protein, human
• Ubiquitin-Protein Ligases
• Nudt21 protein, human
• MED23 protein, human

Topics

• Humans
• 3' Untranslated Regions
• beta Catenin (metabolism)
• Carcinoma, Non-Small-Cell Lung (genetics, radiotherapy)
• Carrier Proteins (metabolism)
• Cleavage And Polyadenylation Specificity Factor (genetics, metabolism)
• Lung Neoplasms (genetics, radiotherapy, metabolism)
• Polyadenylation
• RNA, Long Noncoding (genetics, metabolism)
• Ubiquitin-Protein Ligases (metabolism)