Protein Synthesis Control in Cancer: Selectivity and Therapeutic Targeting

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2022 Mar 22

PMID 35315941

Authors

Joanna R Kovalski

Duygu Kuzuoglu-Ozturk

Davide Ruggero

Affiliations

Soon will be listed here.

Abstract

Translational control of mRNAs is a point of convergence for many oncogenic signals through which cancer cells tune protein expression in tumorigenesis. Cancer cells rely on translational control to appropriately adapt to limited resources while maintaining cell growth and survival, which creates a selective therapeutic window compared to non-transformed cells. In this review, we first discuss how cancer cells modulate the translational machinery to rapidly and selectively synthesize proteins in response to internal oncogenic demands and external factors in the tumor microenvironment. We highlight the clinical potential of compounds that target different translation factors as anti-cancer therapies. Next, we detail how RNA sequence and structural elements interface with the translational machinery and RNA-binding proteins to coordinate the translation of specific pro-survival and pro-growth programs. Finally, we provide an overview of the current and emerging technologies that can be used to illuminate the mechanisms of selective translational control in cancer cells as well as within the microenvironment.

Citing Articles

SIRT1/DNMT3B-mediated epigenetic gene silencing in response to phytoestrogens in mammary epithelial cells.

Ma Y, Boycott C, Zhang J, Gomilar R, Yang T, Stefanska B Epigenetics. 2025; 20(1):2473770.

PMID: 40029260 PMC: 11881848. DOI: 10.1080/15592294.2025.2473770.

Integrating fragment-based screening with targeted protein degradation and genetic rescue to explore eIF4E function.

Sharp S, Martella M, DAgostino S, Milton C, Ward G, Woodhead A Nat Commun. 2025; 15(1):10037.

PMID: 40016190 PMC: 11868579. DOI: 10.1038/s41467-024-54356-1.

RNA-binding proteins as therapeutic targets in cancer.

Jungfleisch J, Gebauer F RNA Biol. 2025; 22(1):1-8.

PMID: 40016176 PMC: 11869776. DOI: 10.1080/15476286.2025.2470511.

Functional screen identifies RBM42 as a mediator of oncogenic mRNA translation specificity.

Kovalski J, Sarioglu G, Subramanyam V, Hernandez G, Rademaker G, Oses-Prieto J Nat Cell Biol. 2025; 27(3):518-529.

PMID: 39905246 DOI: 10.1038/s41556-024-01604-7.

A novel mitochondrial-related risk model for predicting prognosis and immune checkpoint blockade therapy response in uterine corpus endometrial carcinoma.

Liao R, Wang J, Zhang F, Fang Y, Zhou L, Zhang Y Sci Rep. 2025; 15(1):1404.

PMID: 39789247 PMC: 11717914. DOI: 10.1038/s41598-025-85537-7.

References

Hershey J . The role of eIF3 and its individual subunits in cancer. Biochim Biophys Acta. 2014; 1849(7):792-800. DOI: 10.1016/j.bbagrm.2014.10.005. View

Buccitelli C, Selbach M . mRNAs, proteins and the emerging principles of gene expression control. Nat Rev Genet. 2020; 21(10):630-644. DOI: 10.1038/s41576-020-0258-4. View

He P, He C . m A RNA methylation: from mechanisms to therapeutic potential. EMBO J. 2021; 40(3):e105977. PMC: 7849164. DOI: 10.15252/embj.2020105977. View

Zheng X, Cho S, Moon H, Loh T, Jang H, Shen H . Detecting RNA-Protein Interaction Using End-Labeled Biotinylated RNA Oligonucleotides and Immunoblotting. Methods Mol Biol. 2016; 1421:35-44. DOI: 10.1007/978-1-4939-3591-8_4. View

Goodarzi H, Liu X, Nguyen H, Zhang S, Fish L, Tavazoie S . Endogenous tRNA-Derived Fragments Suppress Breast Cancer Progression via YBX1 Displacement. Cell. 2015; 161(4):790-802. PMC: 4457382. DOI: 10.1016/j.cell.2015.02.053. View

Hashimoto S, Furukawa S, Hashimoto A, Tsutaho A, Fukao A, Sakamura Y . ARF6 and AMAP1 are major targets of and mutations to promote invasion, PD-L1 dynamics, and immune evasion of pancreatic cancer. Proc Natl Acad Sci U S A. 2019; 116(35):17450-17459. PMC: 6717289. DOI: 10.1073/pnas.1901765116. View

Gomez-Roman N, Grandori C, Eisenman R, White R . Direct activation of RNA polymerase III transcription by c-Myc. Nature. 2003; 421(6920):290-4. DOI: 10.1038/nature01327. View

Weingarten-Gabbay S, Khan D, Liberman N, Yoffe Y, Bialik S, Das S . The translation initiation factor DAP5 promotes IRES-driven translation of p53 mRNA. Oncogene. 2013; 33(5):611-8. DOI: 10.1038/onc.2012.626. View

Thoreen C, Chantranupong L, Keys H, Wang T, Gray N, Sabatini D . A unifying model for mTORC1-mediated regulation of mRNA translation. Nature. 2012; 485(7396):109-13. PMC: 3347774. DOI: 10.1038/nature11083. View

10.

Kuzuoglu-Ozturk D, Hu Z, Rama M, Devericks E, Weiss J, Chiang G . Revealing molecular pathways for cancer cell fitness through a genetic screen of the cancer translatome. Cell Rep. 2021; 35(13):109321. PMC: 8323864. DOI: 10.1016/j.celrep.2021.109321. View

11.

Gandin V, Masvidal L, Hulea L, Gravel S, Cargnello M, McLaughlan S . nanoCAGE reveals 5' UTR features that define specific modes of translation of functionally related MTOR-sensitive mRNAs. Genome Res. 2016; 26(5):636-48. PMC: 4864462. DOI: 10.1101/gr.197566.115. View

12.

Aviner R, Geiger T, Elroy-Stein O . Novel proteomic approach (PUNCH-P) reveals cell cycle-specific fluctuations in mRNA translation. Genes Dev. 2013; 27(16):1834-44. PMC: 3759699. DOI: 10.1101/gad.219105.113. View

13.

Van Nostrand E, Freese P, Pratt G, Wang X, Wei X, Xiao R . A large-scale binding and functional map of human RNA-binding proteins. Nature. 2020; 583(7818):711-719. PMC: 7410833. DOI: 10.1038/s41586-020-2077-3. View

14.

Wu G, Xu Y, Lau A . Recent insights into eukaryotic translation initiation factors 5A1 and 5A2 and their roles in human health and disease. Cancer Cell Int. 2020; 20:142. PMC: 7191727. DOI: 10.1186/s12935-020-01226-7. View

15.

Calviello L, Venkataramanan S, Rogowski K, Wyler E, Wilkins K, Tejura M . DDX3 depletion represses translation of mRNAs with complex 5' UTRs. Nucleic Acids Res. 2021; 49(9):5336-5350. PMC: 8136831. DOI: 10.1093/nar/gkab287. View

16.

Sobczak K, Krzyzosiak W . Structural determinants of BRCA1 translational regulation. J Biol Chem. 2002; 277(19):17349-58. DOI: 10.1074/jbc.M109162200. View

17.

Sinvani H, Haimov O, Svitkin Y, Sonenberg N, Tamarkin-Ben-Harush A, Viollet B . Translational tolerance of mitochondrial genes to metabolic energy stress involves TISU and eIF1-eIF4GI cooperation in start codon selection. Cell Metab. 2015; 21(3):479-92. DOI: 10.1016/j.cmet.2015.02.010. View

18.

Heerma van Voss M, van Diest P, Raman V . Targeting RNA helicases in cancer: The translation trap. Biochim Biophys Acta Rev Cancer. 2017; 1868(2):510-520. PMC: 5675762. DOI: 10.1016/j.bbcan.2017.09.006. View

19.

Jaiswal P, Koul S, Shanmugam P, Koul H . Eukaryotic Translation Initiation Factor 4 Gamma 1 (eIF4G1) is upregulated during Prostate cancer progression and modulates cell growth and metastasis. Sci Rep. 2018; 8(1):7459. PMC: 5945649. DOI: 10.1038/s41598-018-25798-7. View

20.

Bushell M, Stoneley M, Kong Y, Hamilton T, Spriggs K, Dobbyn H . Polypyrimidine tract binding protein regulates IRES-mediated gene expression during apoptosis. Mol Cell. 2006; 23(3):401-12. DOI: 10.1016/j.molcel.2006.06.012. View