Downregulation of N6-methyladenosine-modified LINC00641 promotes EMT, but provides a ferroptotic vulnerability in lung cancer.
Downregulation of N6-methyladenosine-modified LINC00641 promotes EMT, but provides a ferroptotic vulnerability in lung cancer.
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DOI：
10.1038/s41419-023-05880-3
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发表时间：
2023-06-13
影响因子：
9
通讯作者：
Yuan, Shuai
中科院分区：
文献类型：
--
作者：
Xi, Shu;Ming, Dao-Jing;Zhang, Jin-Hui;Guo, Meng-Meng;Wang, Shuang-Ying;Cai, Yi;Liu, Meng-Yang;Wang, Dan-Qi;Zhang, Yi-Jie;Li, Yafei;Yuan, Shuai
肺癌的预后很差，有效的治疗方法很少。靶向铁凋亡是肿瘤治疗的一个新的有前途的策略。LINC 00641已经参与了几种癌症，然而，它在肺癌治疗中的具体作用在很大程度上仍然未知。在这里，我们报道了LINC 00641在肿瘤组织中下调，并且其下调与肺腺癌的不良结局相关。LINC 00641主要定位于细胞核中，并被m6 A修饰。核m6 A阅读器YTHDC 1通过影响其稳定性来调节LINC 00641的表达。我们证明LINC 00641通过抑制体外迁移和侵袭以及体内转移来抑制肺癌。LINC 00641的敲低上调了HuR蛋白水平（尤其是在细胞质中），随后通过稳定其mRNA来增加N-钙粘蛋白水平，然后最终促进EMT。有趣的是，LINC 00641在肺癌细胞中的敲低增加了花生四烯酸代谢并促进了铁凋亡敏感性。我们的研究结果表明LINC 00641通过抑制EMT而成为肿瘤抑制剂。在另一方面，LINC 00641的低表达引起肺癌细胞中的铁凋亡脆弱性，其可充当肺癌的潜在铁凋亡相关治疗靶标。
The prognosis of lung cancer is poor with few effective therapies. Targeting ferroptosis is a new promising strategy for cancer therapy. LINC00641 has been involved in several cancers, however, its specific roles in lung cancer treatment remain largely unknown. Here, we reported that LINC00641 was down-regulated in tumor tissues and its downregulation was associated with poor outcomes in lung adenocarcinoma. LINC00641 was localized primarily in the nucleus and was modified by m6A. The nuclear m6A reader YTHDC1 regulated LINC00641 expression by affecting its stability. We demonstrated that LINC00641 suppressed lung cancer by inhibiting migration and invasion in vitro and metastasis in vivo. Knockdown of LINC00641 upregulated HuR protein level (especially in the cytoplasm), which subsequently increased N-cadherin levels by stabilizing its mRNA, then ultimately promoted EMT. Interestingly, LINC00641 knockdown in lung cancer cells increased the arachidonic acid metabolism and promoted ferroptosis sensitivity. Our findings identified LINC00641 as a tumor suppressor through inhibiting EMT. In another aspect, low expression of LINC00641 caused a ferroptotic vulnerability in lung cancer cells, which may serve as a potential ferroptosis-related therapeutic target for lung cancer.
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