eIF4E S209 phosphorylation licenses myc- and stress-driven oncogenesis
Hang Ruan,
Xiangyun Li,
Xiang Xu,
Brian J Leibowitz,
Jingshan Tong,
Lujia Chen,
Luoquan Ao,
Wei Xing,
Jianhua Luo,
Yanping Yu,
Robert E Schoen,
Nahum Sonenberg,
Xinghua Lu,
Lin Zhang,
Jian Yu
Affiliations
Hang Ruan
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, United States; UPMC Hillman Cancer Center, Pittsburgh, United States
Xiangyun Li
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, United States; UPMC Hillman Cancer Center, Pittsburgh, United States; Department of Stem cell and regenerative medicine, Daping Hospital, Army Medical University, Chongqing, China
Xiang Xu
Department of Stem cell and regenerative medicine, Daping Hospital, Army Medical University, Chongqing, China; Central laboratory, State key laboratory of trauma, burn and combined Injury, Daping Hospital, Chongqing, China
Brian J Leibowitz
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, United States; UPMC Hillman Cancer Center, Pittsburgh, United States
Jingshan Tong
UPMC Hillman Cancer Center, Pittsburgh, United States; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States
Lujia Chen
UPMC Hillman Cancer Center, Pittsburgh, United States; Department of Biomedical informatics, University of Pittsburgh School of Medicine, Pittsburgh, United States
Luoquan Ao
Department of Stem cell and regenerative medicine, Daping Hospital, Army Medical University, Chongqing, China; Central laboratory, State key laboratory of trauma, burn and combined Injury, Daping Hospital, Chongqing, China
Wei Xing
Department of Stem cell and regenerative medicine, Daping Hospital, Army Medical University, Chongqing, China; Central laboratory, State key laboratory of trauma, burn and combined Injury, Daping Hospital, Chongqing, China
Jianhua Luo
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, United States
Yanping Yu
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, United States
Robert E Schoen
Departments of Medicine and Epidemiology, University of Pittsburgh, Pittsburgh, United States
UPMC Hillman Cancer Center, Pittsburgh, United States; Department of Biomedical informatics, University of Pittsburgh School of Medicine, Pittsburgh, United States
Lin Zhang
UPMC Hillman Cancer Center, Pittsburgh, United States; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States
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.
