TY - JOUR TI - eIF4E S209 phosphorylation licenses myc- and stress-driven oncogenesis AU - Ruan, Hang AU - Li, Xiangyun AU - Xu, Xiang AU - Leibowitz, Brian J AU - Tong, Jingshan AU - Chen, Lujia AU - Ao, Luoquan AU - Xing, Wei AU - Luo, Jianhua AU - Yu, Yanping AU - Schoen, Robert E AU - Sonenberg, Nahum AU - Lu, Xinghua AU - Zhang, Lin AU - Yu, Jian A2 - Murphy, Maureen E A2 - El-Deiry, Wafik S A2 - Wang, Zhenghe J VL - 9 PY - 2020 DA - 2020/11/02 SP - e60151 C1 - eLife 2020;9:e60151 DO - 10.7554/eLife.60151 UR - https://doi.org/10.7554/eLife.60151 AB - To better understand a role of eIF4E S209 in oncogenic translation, we generated EIF4ES209A/+ heterozygous knockin (4EKI) HCT 116 human colorectal cancer (CRC) cells. 4EKI had little impact on total eIF4E levels, cap binding or global translation, but markedly reduced HCT 116 cell growth in spheroids and mice, and CRC organoid growth. 4EKI strongly inhibited Myc and ATF4 translation, the integrated stress response (ISR)-dependent glutamine metabolic signature, AKT activation and proliferation in vivo. 4EKI inhibited polyposis in ApcMin/+ mice by suppressing Myc protein and AKT activation. Furthermore, p-eIF4E was highly elevated in CRC precursor lesions in mouse and human. p-eIF4E cooperated with mutant KRAS to promote Myc and ISR-dependent glutamine addiction in various CRC cell lines, characterized by increased cell death, transcriptomic heterogeneity and immune suppression upon deprivation. These findings demonstrate a critical role of eIF4E S209-dependent translation in Myc and stress-driven oncogenesis and as a potential therapeutic vulnerability. KW - eIF4E S209 KW - Myc KW - KRAS KW - the integrated stress response KW - glutamine KW - colon cancer JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -