YTHDC1 as a tumor progression suppressor through modulating FSP1-dependent ferroptosis suppression in lung cancer
YTHDC1 as a tumor progression suppressor through modulating FSP1-dependent ferroptosis suppression in lung cancer
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DOI：
10.1038/s41418-023-01234-w
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发表时间：
2023-10-30
影响因子：
12.4
通讯作者：
Hu，Hailiang
中科院分区：
文献类型：
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作者：
Yuan，Shuai;Xi，Shu;Hu，Hailiang
铁凋亡是一种由铁依赖性磷脂过氧化引发的受调控的细胞死亡过程，主要受gpx4依赖性和fsp1依赖性监视机制的抑制。然而，在癌症发展过程中，铁下垂监测系统是如何被调节的，这在很大程度上仍然是未知的。在这里，我们报道了YTHDC1介导的FSP1的m6A表观遗传调控减轻了FSP1依赖性的铁凋亡抑制，这在一定程度上有助于YTHDC1在肺癌进展中的肿瘤抑制作用。YTHDC1敲低促进肺癌肿瘤进展，上调FSP1蛋白水平，导致肺癌细胞耐铁下垂。沉默FSP1可消除YTHDC1敲低诱导的增殖增加和铁下垂抗性。在机制上，YTHDC1结合到fsp13 ' -UTR中的m6A位点，招募了备选的聚腺苷化调节因子CSTF3，从而产生较不稳定的较短的3 ' -UTR中包含的fsp1mrna，而YTHDC1下调产生较长的3 ' -UTR中包含的fsp1mrna，该mrna被RNA结合蛋白HuR稳定，从而导致FSP1蛋白水平升高。因此，我们的研究结果确定YTHDC1是肺癌的肿瘤进展抑制因子，并通过调节fsp1mrna的稳定性来调节铁下垂，从而为YTHDC1高含量肺癌的铁下垂相关治疗提供了选择。
Ferroptosis is a regulated cell death process initiated by iron-dependent phospholipid peroxidation and is mainly suppressed by GPX4-dependent and FSP1-dependent surveillance mechanisms. However, how the ferroptosis surveillance system is regulated during cancer development remains largely unknown. Here, we report that the YTHDC1-mediated m6A epigenetic regulation of FSP1 alleviates the FSP1-dependent ferroptosis suppression that partially contributes to the tumor suppressive role of YTHDC1 in lung cancer progression. YTHDC1 knockdown promoted the lung tumor progression and upregulated FSP1 protein level that resulted in ferroptosis resistance of lung cancer cells. Silencing FSP1 abrogated YTHDC1 knockdown-induced proliferation increase and ferroptosis resistance. Mechanistically, YTHDC1 binding to the m6A sites in theFSP13’-UTR recruited the alternative polyadenylation regulator CSTF3 to generate a less stable shorter 3’-UTR containedFSP1mRNA, whereas YTHDC1 downregulation generated the longer 3’-UTR containedFSP1mRNA that is stabilized by RNA binding protein HuR and thus led to the enhanced FSP1 protein level. Therefore, our findings identify YTHDC1 as a tumor progression suppressor in lung cancer and a ferroptosis regulator through modulating theFSP1mRNA stability and thus suggest a ferroptosis-related therapeutic option for YTHDC1highlung cancer.