2. Academic Validation
  3. N6-methyladenosine-mediated upregulation of LNCAROD confers radioresistance in esophageal squamous cell carcinoma through stabilizing PARP1

N6-methyladenosine-mediated upregulation of LNCAROD confers radioresistance in esophageal squamous cell carcinoma through stabilizing PARP1

  • Clin Transl Med. 2024 Oct;14(10):e70039. doi: 10.1002/ctm2.70039.
Xiaobo Shi 1 2,  Xiaozhi Zhang 2,  Xinran Huang 1,  Ruijuan Zhang 1,  Shupei Pan 1,  Shan Huang 1,  Yuchen Wang 1,  Yue Ke 1,  Wei Guo 1,  Xiaoxiao Liu 1,  Yu Hao 1,  You Li 3,  Xu Zhao 2,  Yuchen Sun 2,  Jing Li 2,  Hongbing Ma 1,  Xixi Zhao 1
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 2 Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 3 Department of Peripheral Vascular, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
PMID: 39367700 DOI: 10.1002/ctm2.70039
Abstract

Background: Radiotherapy is a primary therapeutic modality for esophageal squamous cell carcinoma (ESCC), but its effectiveness is still restricted due to the resistance of Cancer cells to radiation. Long non-coding RNAs (lncRNAs) and N6-methyladenosine (m6A) have been shown to play significant roles in tumour radioresistance. However, the precise manifestation and role of m6A-modified lncRNAs in ESCC radioresistance remain unclear.

Methods: Bioinformatics analysis was conducted to identify m6A-modified lncRNAs implicated in the radioresistance of ESCC. A series of functional experiments were performed to investigate the function of LNCAROD in ESCC. Methylated RNA immunoprecipitation, chromatin isolation by RNA purification-mass spectrometry, RNA immunoprecipitation, and co-immunoprecipitation experiments were performed to explore the mechanism of m6A-mediated upregulation of LNCAROD expression and the downstream mechanism enhancing the radioresistance of ESCC. The efficacy of LNCAROD in vivo was assessed using murine xenograft models.

Results: Herein, we identified LNCAROD as a novel METTL3-mediated lncRNA that enhanced radioresistance in ESCC cells and was post-transcriptionally stabilised by YTHDC1. Moreover, we confirmed that LNCAROD prevented ubiquitin-proteasome degradation of PARP1 protein by facilitating PARP1-NPM1 interaction, thereby contributing to homologous recombination-mediated DNA double-strand breaks repair and enhancing the radiation resistance of ESCC cells. Silencing LNCAROD in a nude mouse model of ESCC in vivo resulted in slower tumour growth and increased radiosensitivity.

Conclusion: Our findings enhance the understanding of m6A-modified lncRNA-driven machinery in ESCC radioresistance and underscore the significance of LNCAROD in this context, thereby contributing to the development of a potential therapeutic target for ESCC patients.

Keywords

LNCAROD; N6‐methyladenosine; PARP1; esophageal squamous cell carcinoma; radioresistance.

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