Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, China.
Cell Death Dis. 2024 Aug 21;15(8):608. doi: 10.1038/s41419-024-07000-1.
Recently, various cancer types have been identified to express a distinct subset of Interferon-stimulated genes (ISGs) that mediate therapy resistance. The mechanism through which cancer cells maintain prolonged Interferon stimulation effects to coordinate resistance remains unclear. Our research demonstrated that aberrant upregulation of TAGLN2 is associated with gastric cancer progression, and inhibiting its expression renders gastric cancer cells more susceptible to chemotherapy and radiation. We uncovered a novel role for TAGLN2 in the upregulation of resistance signature ISGs by enhancing YBX1-associated ssDNA aggregation and cGAS-STING pathway activation. TAGLN2 modulates YBX1 by recruiting c-Myc and SOX9 to YBX1 promoter region and directly interacting with AKT-YBX1, thereby enhancing YBX1 phosphorylation and nuclear translocation. Significantly, targeted downregulation of key proteins, inhibition of the TAGLN2-YBX1-AKT interaction (using Fisetin or MK2206) or disruption of the cGAS-STING pathway substantially reduced ssDNA accumulation, subsequent ISGs upregulation, and therapy resistance. The combination of Cisplatin with MK2206 displayed a synergistic effect in the higher TAGLN2-expressing xenograft tumors. Clinical analysis indicated that a derived nine-gene set effectively predicts therapeutic sensitivity and long-term prognosis in gastric cancer patients. These findings suggest that TAGLN2, YBX1 and induced ISGs are novel predictive markers for clinical outcomes, and targeting this axis is an attractive therapeutic sensitization strategy.
最近，研究发现多种癌症类型表达独特的干扰素刺激基因（ISGs）亚群，这些基因介导治疗耐药性。癌细胞维持干扰素刺激作用以协调耐药性的机制尚不清楚。我们的研究表明，TAGLN2 的异常上调与胃癌的进展相关，抑制其表达可使胃癌细胞对化疗和放疗更敏感。我们揭示了 TAGLN2 通过增强 YBX1 相关单链 DNA 聚集和 cGAS-STING 通路激活来上调耐药特征 ISGs 的新作用。TAGLN2 通过招募 c-Myc 和 SOX9 到 YBX1 启动子区域并与 AKT-YBX1 直接相互作用来调节 YBX1，从而增强 YBX1 的磷酸化和核易位。重要的是，靶向下调关键蛋白、抑制 TAGLN2-YBX1-AKT 相互作用（使用 Fisetin 或 MK2206）或破坏 cGAS-STING 通路可显著减少单链 DNA 积累、随后的 ISGs 上调和耐药性。顺铂与 MK2206 联合使用在高表达 TAGLN2 的异种移植肿瘤中显示出协同作用。临床分析表明，一个衍生的九基因集可有效预测胃癌患者的治疗敏感性和长期预后。这些发现表明，TAGLN2、YBX1 和诱导的 ISGs 是临床结局的新型预测标志物，靶向该轴是一种有吸引力的治疗增敏策略。
