YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression
YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression
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YTHDF1 将缺氧适应与非小细胞肺癌进展联系起来
DOI：
10.1038/s41467-019-12801-6
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发表时间：
2019-10-25
影响因子：
16.6
通讯作者：
Chen, Yongbin
中科院分区：
文献类型：
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作者：
Shi, Yulin;Fan, Songqing;Chen, Yongbin
低氧在高海拔地区自然发生，低氧实体瘤在病理上也会发生。在这里，我们报告了与各种人类癌症相关的基因在藏族人和6种藏族家养哺乳动物中的进化速度比同等的低地动物快。此外，m6A修饰的mRNA结合蛋白YTHDF1是进化上积极选择的高原适应基因之一，在包括非小细胞肺癌(NSCLC)在内的各种癌症中被扩增。我们发现YTHDF1缺乏通过调节CDK2、CDK4和细胞周期蛋白D1的翻译效率来抑制NSCLC细胞的增殖和异种移植瘤的形成，并且YTHDF1缺失抑制了新发肺腺癌(ADC)的进展。然而，我们观察到YTHDF1的高表达与更好的临床结果相关，它的耗竭导致癌细胞对顺铂(DDP)治疗产生耐药性。机制研究证实Keap1-Nrf2-AKR1c1轴是YTHDF1的下游调节因子。总之，这些发现强调了YTHDF1在低氧适应和非小细胞肺癌发病机制中的关键作用。
Hypoxia occurs naturally at high-altitudes and pathologically in hypoxic solid tumors. Here, we report that genes involved in various human cancers evolved rapidly in Tibetans and six Tibetan domestic mammals compared to reciprocal lowlanders. Furthermore, m6A modified mRNA binding protein YTHDF1, one of evolutionary positively selected genes for high-altitude adaptation is amplified in various cancers, including non-small cell lung cancer (NSCLC). We show that YTHDF1 deficiency inhibits NSCLC cell proliferation and xenograft tumor formation through regulating the translational efficiency of CDK2, CDK4, and cyclin D1, and that YTHDF1 depletion restrains de novo lung adenocarcinomas (ADC) progression. However, we observe that YTHDF1 high expression correlates with better clinical outcome, with its depletion rendering cancerous cells resistant to cisplatin (DDP) treatment. Mechanistic studies identified the Keap1-Nrf2-AKR1C1 axis as the downstream mediator of YTHDF1. Together, these findings highlight the critical role of YTHDF1 in both hypoxia adaptation and pathogenesis of NSCLC.