Chen Shizhen, Zhuo Amei, Tang Renyu, Su Siming, Wen Binbin, Wei Wujun, Xie Jianjiang, Yu Ziqi, Rao Boqi, Lu Jiachun, Deng Yibin, Zhang Zhili, Yang Lei
The Key Laboratory of Advanced Interdisciplinary Studies, School of Public healthy, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Key Laboratory of Clinical Molecular Diagnosis and Research for High Incidence Diseases in Western Guangxi Universities, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China.
Commun Biol. 2025 Sep 2;8(1):1333. doi: 10.1038/s42003-025-08776-4.
Adenosine-to-inosine (A-to-I) RNA editing is a critical post-transcriptional modification that enhances tumor genome diversity and contributes to cancer progression. In non-small cell lung cancer (NSCLC), while specific A-to-I editing events have been identified, their functional mechanisms and clinical relevance remain poorly understood. Here, through whole-transcriptome analysis of NSCLC specimens, we discovered a hyper-editing event at position c.1746 in the long non-coding RNA SNHG3 (c.1746 A > I), which correlates with advanced metastatic stages and reduced patient survival. Functional studies demonstrated that edited SNHG3 (SNHG3) exhibits significantly greater pro-metastatic activity compared to its wild-type counterpart (SNHG3). Mechanistically, SNHG3 shows enhanced binding affinity for the chromatin remodeler SSRP1, triggering SSRP1-mediated replication origin assembly and subsequent upregulation of fatty acid metabolism and ferroptosis-related genes. This molecular rewiring promotes fatty acid oxidation, confers resistance to ferroptosis, and importantly, drives docetaxel (DTX) chemoresistance. In DTX-resistant NSCLC cell lines, patient-derived organoids, and Nude mouse xenograft tumor model, antisense oligonucleotide-based targeting of SNHG3 effectively restored DTX sensitivity and suppressed tumor growth. Our findings demonstrate that SNHG3 c.1746 A > I editing serves both as a novel prognostic biomarker for NSCLC and as a mechanistically defined therapeutic target to overcome DTX resistance, which offers a potential therapeutic target to improve DTX efficacy.
腺苷到肌苷（A-to-I）RNA编辑是一种关键的转录后修饰，可增强肿瘤基因组多样性并促进癌症进展。在非小细胞肺癌（NSCLC）中，虽然已鉴定出特定的A-to-I编辑事件，但其功能机制和临床相关性仍知之甚少。在这里，通过对NSCLC标本进行全转录组分析，我们在长链非编码RNA SNHG3的c.1746位置发现了一个超编辑事件（c.1746 A > I），该事件与晚期转移阶段和患者生存率降低相关。功能研究表明，与野生型对应物（SNHG3）相比，编辑后的SNHG3（SNHG3）表现出明显更强的促转移活性。从机制上讲，SNHG3对染色质重塑因子SSRP1的结合亲和力增强，触发了SSRP1介导的复制起点组装以及随后脂肪酸代谢和铁死亡相关基因的上调。这种分子重排促进脂肪酸氧化，赋予对铁死亡的抗性，重要的是，导致多西他赛（DTX）耐药。在DTX耐药的NSCLC细胞系、患者来源的类器官和裸鼠异种移植肿瘤模型中，基于反义寡核苷酸靶向SNHG3可有效恢复DTX敏感性并抑制肿瘤生长。我们的研究结果表明，SNHG3 c.1746 A > I编辑既是NSCLC的一种新型预后生物标志物，也是一个通过机制定义的克服DTX耐药性的治疗靶点，这为提高DTX疗效提供了一个潜在的治疗靶点。
