YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression

Yulin Shi, Songqing Fan, Mengge Wu, Zhixiang Zuo, Xingyang Li, Liping Jiang, Qiushuo Shen, Peifang Xu, Lin Zeng, Yongchun Zhou, Yunchao Huang, Zuozhang Yang, Jumin Zhou, Jing Gao, Hu Zhou, Shuhua Xu, Hongbin Ji, Peng Shi, Dong-Dong Wu (), Cuiping Yang () and Yongbin Chen ()
Additional contact information
Yulin Shi: Kunming Institute of Zoology
Songqing Fan: Central South University
Mengge Wu: Kunming Medical University
Zhixiang Zuo: Sun Yat-sen University
Xingyang Li: Sun Yat-sen University
Liping Jiang: Kunming Institute of Zoology
Qiushuo Shen: Kunming Institute of Zoology
Peifang Xu: Kunming Institute of Zoology
Lin Zeng: Kunming Institute of Zoology
Yongchun Zhou: Kunming Medical University
Yunchao Huang: Kunming Medical University
Zuozhang Yang: Kunming Medical University
Jumin Zhou: Kunming Institute of Zoology
Jing Gao: Chinese Academy of Sciences
Hu Zhou: Chinese Academy of Sciences
Shuhua Xu: Chinese Academy of Sciences
Hongbin Ji: Chinese Academy of Sciences
Peng Shi: Chinese Academy of Sciences
Dong-Dong Wu: Chinese Academy of Sciences
Cuiping Yang: Kunming Institute of Zoology
Yongbin Chen: Kunming Institute of Zoology

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-12801-6

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