Rpl24Bst mutation suppresses colorectal cancer by promoting eEF2 phosphorylation via eEF2K
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Evaluation Summary:
In this study, Knight and colleagues investigate the role of the ribosome and translational control in colorectal tumours. A mutation of a protein of the large ribosomal subunit, RPL24, is used to suppress tumours driven by two mutations found commonly in cancer, in APC and KRAS. The authors identify a mechanistic output of the RPL24 BST mutation, eEF2 phosphorylation, which they demonstrate is a major effector in inhibiting tumour cell translation and proliferation. By targeting the eEF2 kinase eEF2K, they restore protein synthesis in RPL24 mutant cells. The conclusion is well supported by the experimental data presented, which implies that translation elongation can be a potential therapeutic target of KRAS mutated CRC. Importantly, Rpl24Bst in wildtype intestine does not affect epithelial cell proliferation and differentiation, suggesting that translation elongation can be used as tumour-specific target.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Abstract
Increased protein synthesis supports the rapid cell proliferation associated with cancer. The Rpl24 Bst mutant mouse reduces the expression of the ribosomal protein RPL24 and has been used to suppress translation and limit tumorigenesis in multiple mouse models of cancer. Here, we show that Rpl24 Bst also suppresses tumorigenesis and proliferation in a model of colorectal cancer (CRC) with two common patient mutations, Apc and Kras . In contrast to previous reports, Rpl24 Bst mutation has no effect on ribosomal subunit abundance but suppresses translation elongation through phosphorylation of eEF2, reducing protein synthesis by 40% in tumour cells. Ablating eEF2 phosphorylation in Rpl24 Bst mutant mice by inactivating its kinase, eEF2K, completely restores the rates of elongation and protein synthesis. Furthermore, eEF2K activity is required for the Rpl24 Bst mutant to suppress tumorigenesis. This work demonstrates that elevation of eEF2 phosphorylation is an effective means to suppress colorectal tumorigenesis with two driver mutations. This positions translation elongation as a therapeutic target in CRC, as well as in other cancers where the Rpl24 Bst mutation has a tumour suppressive effect in mouse models.
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Evaluation Summary:
In this study, Knight and colleagues investigate the role of the ribosome and translational control in colorectal tumours. A mutation of a protein of the large ribosomal subunit, RPL24, is used to suppress tumours driven by two mutations found commonly in cancer, in APC and KRAS. The authors identify a mechanistic output of the RPL24 BST mutation, eEF2 phosphorylation, which they demonstrate is a major effector in inhibiting tumour cell translation and proliferation. By targeting the eEF2 kinase eEF2K, they restore protein synthesis in RPL24 mutant cells. The conclusion is well supported by the experimental data presented, which implies that translation elongation can be a potential therapeutic target of KRAS mutated CRC. Importantly, Rpl24Bst in wildtype intestine does not affect epithelial cell proliferation and …
Evaluation Summary:
In this study, Knight and colleagues investigate the role of the ribosome and translational control in colorectal tumours. A mutation of a protein of the large ribosomal subunit, RPL24, is used to suppress tumours driven by two mutations found commonly in cancer, in APC and KRAS. The authors identify a mechanistic output of the RPL24 BST mutation, eEF2 phosphorylation, which they demonstrate is a major effector in inhibiting tumour cell translation and proliferation. By targeting the eEF2 kinase eEF2K, they restore protein synthesis in RPL24 mutant cells. The conclusion is well supported by the experimental data presented, which implies that translation elongation can be a potential therapeutic target of KRAS mutated CRC. Importantly, Rpl24Bst in wildtype intestine does not affect epithelial cell proliferation and differentiation, suggesting that translation elongation can be used as tumour-specific target.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
The manuscript by Knight et al. show that the ribosomal protein RPL24 regulates protein synthesis and tumour proliferation, while reduced expression of RPL24 suppresses KRAS mutated colorectal cancer (CRC) via reduced translation elongation. The manuscript is well written and the experimental design is very thorough that combines a number of preclinical models and biochemical assays to demonstrate that Rpl24Bst slows down translation elongation and suppresses tumour growth via increased eEF2 phosphorylation. The conclusion is well supported by the experimental data presented, which implies that translation elongation can be a potential therapeutic target of KRAS mutated CRC. Importantly, Rpl24Bst in wildtype intestine does not affect epithelial cell proliferation and differentiation, suggesting that …
Reviewer #1 (Public Review):
The manuscript by Knight et al. show that the ribosomal protein RPL24 regulates protein synthesis and tumour proliferation, while reduced expression of RPL24 suppresses KRAS mutated colorectal cancer (CRC) via reduced translation elongation. The manuscript is well written and the experimental design is very thorough that combines a number of preclinical models and biochemical assays to demonstrate that Rpl24Bst slows down translation elongation and suppresses tumour growth via increased eEF2 phosphorylation. The conclusion is well supported by the experimental data presented, which implies that translation elongation can be a potential therapeutic target of KRAS mutated CRC. Importantly, Rpl24Bst in wildtype intestine does not affect epithelial cell proliferation and differentiation, suggesting that translation elongation can be used as tumour-specific target.
Overall, the work is of high quality with impressive amount of work. However, it remains unclear why and how the tumour suppressive role of Rpl24Bst is specific to KRAS G12D mutation only, considering that increased eEF2 phosphorylation is also observed in the KRAS wildtype model.
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Reviewer #2 (Public Review):
In this study, Knight and colleagues investigate the role of the ribosome and translational control in colorectal tumours. A mutation of a protein of the large ribosomal subunit, RPL24, is used to suppress tumours driven by two mutations found commonly in cancer, in Apc and Kras. Knight et al identify a mechanistic output of the RPL24 BST mutation, eEF2 phosphorylation, which they demonstrate is a major effector in inhibiting tumour cell translation and proliferation. By targeting the eEF2 kinase eEF2K, they restore protein synthesis in RPL24 mutant cells. This work enhances the concept of targeting translational control in tumours.
The strengths are the tumour assays including the genetic experiments which identify the role of eEF2 phosphorylation inhibiting tumour formation, including targeting the kinase, …
Reviewer #2 (Public Review):
In this study, Knight and colleagues investigate the role of the ribosome and translational control in colorectal tumours. A mutation of a protein of the large ribosomal subunit, RPL24, is used to suppress tumours driven by two mutations found commonly in cancer, in Apc and Kras. Knight et al identify a mechanistic output of the RPL24 BST mutation, eEF2 phosphorylation, which they demonstrate is a major effector in inhibiting tumour cell translation and proliferation. By targeting the eEF2 kinase eEF2K, they restore protein synthesis in RPL24 mutant cells. This work enhances the concept of targeting translational control in tumours.
The strengths are the tumour assays including the genetic experiments which identify the role of eEF2 phosphorylation inhibiting tumour formation, including targeting the kinase, eEF2K. This places eEF2 phosphorylation as a critical node in translational control in tumours. This work is timely in identifying this pathway as a therapeutic target for further dissection. What is yet to be discovered is how RPL24-bst induces eEF2-phosphorylation. It is unclear how direct this mechanism is and whether it involves ribosome heterogeneity and/or translational stress.
Overall a significant study identifying a novel target to explore in colorectal cancer.
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