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.
Highlights
Hypoxia occurs naturally at high-altitudes and pathologically in hypoxic solid tumors
We find that YTHDF1 low expression correlates with a worse clinical outcome by rendering cancerous cells resistant to cisplatin treatment through upregulating an antioxidant system which is Keap1-NF-E2 p45-related factor 2 (Nrf2)-AKR1C1 dependent, and demonstrate that the resistance of hypoxia-induced cellular apoptosis in YTHDF1 knockdown BEAS-2B cells utilizes the same axis
As hypoxia is a driving force of tumor progression and metastasis by influencing the expression of many tumor-associated genes (TAGs), we investigated the evolutionary pattern of genes involved in various cancers in human and six Tibetan domestic mammals at high altitude
Summary
Hypoxia occurs naturally at high-altitudes and pathologically in hypoxic solid tumors. M6A modified mRNA binding protein YTHDF1, one of evolutionary positively selected genes for highaltitude adaptation is amplified in various cancers, including non-small cell lung cancer (NSCLC). Coding gene EGLN1, where adaptive amino acid changing mutations increased HIF-2α degradation to reduce the hemoglobin (Hb) concentration in Tibetans, protecting them from polycythemia, a condition considered as a blunted physiological response at high altitude[6] Consistent with this observation, recent studies showed that the Tibetan specific HIF-2α adaptive mutation down regulates its own expression[7,8]. Burrowing rodents like naked and blind mole rats living under extreme hypoxic conditions evolve strong hypoxic tolerance and cancer resistance, and could reveal molecular events important for cancer progression[11,12], suggests that we can use evolutionary theory to identify genes involved in both hypoxia adaptation and hypoxic solid tumors. This study provides insights into adaptive evolution, and the search for therapeutic targets for cancers
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