eIF4E S209 phosphorylation licenses Myc-and stress-driven oncogenesis
- University of Pittsburgh, United States
- Daping Hospital, China
- McGill University, Canada
Abstract
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 on total eIF4E levels, cap binding or global translation, while 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.
Data availability
Microarray data is deposited in Dryad under doi:10.5061/dryad.tb2rbnzxm.All data generated or analyzed during this study are included in the manuscript and supporting files.
-
Microarray dataDryad Digital Repository, doi:10.5061/dryad.tb2rbnzxm.
Article and author information
Author details
Funding
NIH (R01CA215481)
- Jian Yu
NIH (R01CA172136)
- Lin Zhang
NIH (R01CA203028)
- Lin Zhang
NIH (R01CA236271)
- Lin Zhang
NIH (R01LM012011)
- Xinghua Lu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (# 19085635 and 18063020) of the University of Pittsburgh. All animal experiments were approved by the University of Pittsburgh Institutional Animal Care and Use Committee under Animal welfare assurance number A-3187-01. No surgery or invasive procedure was performed and every effort was made to minimize suffering with humane sacrifice.
Copyright
© 2020, Ruan et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,357
- views
-
- 361
- downloads
-
- 25
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
eIF4E S209 phosphorylation licenses Myc-and stress-driven oncogenesis
eLife 9:e60151.
https://doi.org/10.7554/eLife.60151
Further reading
-
- Cancer Biology
TAK1 is a serine/threonine protein kinase that is a key regulator in a wide variety of cellular processes. However, the functions and mechanisms involved in cancer metastasis are still not well understood. Here, we found that TAK1 knockdown promoted esophageal squamous cancer carcinoma (ESCC) migration and invasion, whereas TAK1 overexpression resulted in the opposite outcome. These in vitro findings were recapitulated in vivo in a xenograft metastatic mouse model. Mechanistically, co-immunoprecipitation and mass spectrometry demonstrated that TAK1 interacted with phospholipase C epsilon 1 (PLCE1) and phosphorylated PLCE1 at serine 1060 (S1060). Functional studies revealed that phosphorylation at S1060 in PLCE1 resulted in decreased enzyme activity, leading to the repression of phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis. As a result, the degradation products of PIP2 including diacylglycerol (DAG) and inositol IP3 were reduced, which thereby suppressed signal transduction in the axis of PKC/GSK-3β/β-Catenin. Consequently, expression of cancer metastasis-related genes was impeded by TAK1. Overall, our data indicate that TAK1 plays a negative role in ESCC metastasis, which depends on the TAK1-induced phosphorylation of PLCE1 at S1060.
-
- Cancer Biology
- Cell Biology
Cell crowding causes high-grade breast cancer cells to become more invasive by activating a molecular switch that causes the cells to shrink and spread.
