YTHDF1 Links Hypoxia Adaptation and Non-Small Cell Lung Cancer Progression

Nat Commun. 2019 Oct 25;10(1):4892. doi: 10.1038/s41467-019-12801-6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological / genetics
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / metabolism
  • Altitude*
  • Animals
  • Animals, Domestic
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Case-Control Studies
  • Cattle
  • Cyclin D1 / genetics
  • Cyclin-Dependent Kinase 2 / genetics
  • Cyclin-Dependent Kinase 4 / genetics
  • Dogs
  • Evolution, Molecular
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / genetics
  • Genome
  • Goats
  • Horses
  • Humans
  • Hypoxia / genetics*
  • Hypoxia / metabolism
  • Lung / metabolism
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Mice
  • Neoplasm Transplantation
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Sheep
  • Sus scrofa
  • Swine
  • Tibet
  • Tumor Hypoxia / genetics

Substances

  • RNA-Binding Proteins
  • YTHDF1 protein, human
  • Cyclin D1
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 4