2. Academic Validation
  3. LINC00921 reduces lung cancer radiosensitivity by destabilizing NUDT21 and driving aberrant MED23 alternative polyadenylation

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

  • Cell Rep. 2023 Nov 23;42(12):113479. doi: 10.1016/j.celrep.2023.113479.
Nasha Zhang 1,  Xijun Liu 2,  Linying Huang 2,  Jiajia Zeng 2,  Chi Ma 2,  Linyu Han 2,  Wenwen Li 2,  Jinming Yu 3,  Ming Yang 4
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention, and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.
  • 2 Department of Radiation Oncology, Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
  • 3 Department of Radiation Oncology, Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China; Shandong University Cancer Center, Jinan, Shandong, China. Electronic address: [email protected].
  • 4 Department of Radiation Oncology, Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China; Shandong University Cancer Center, Jinan, Shandong, China. Electronic address: [email protected].
PMID: 37999979 DOI: 10.1016/j.celrep.2023.113479
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.

Keywords

CP: Cancer; CP: Molecular biology; LINC00921; MED13L; NUDT21; alternative polyadenylation; lung cancer; radiotherapy.

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