The Role of Translation Control in Tumorigenesis and Its Therapeutic Implications

Yichen Xu,Davide Ruggero

doi:10.1146/annurev-cancerbio-030419-033420

Yichen Xu, Davide Ruggero

Open Access

https://doi.org/10.1146/annurev-cancerbio-030419-033420

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Abstract

As a convergent mechanism downstream of most oncogenic signals, control of mRNA translation has emerged as a key driver in establishing and tuning gene expression at specific steps in cancer development. Translation control is the most energetically expensive molecular process in the cell that needs to be modulated upon adaption to limited cellular resources, such as cellular stress. It thereby serves as the Achilles’ heel for cancer cells, particularly in response to changes in the microenvironment as well as to nutrient and metabolic shifts characteristic of cancer cell growth and metastasis. In this review, we discuss emerging discoveries that reveal how cancer cells modulate the translation machinery to adapt to oncogenic stress, the mechanisms that guide mRNA translation specificity in cancer, and how this selective mode of gene regulation provides advantages for cancer progression. We also provide an overview of promising preclinical and clinical efforts aimed at targeting the unique vulnerabilities of cancer cells that rely on the remodeling of mRNA translation for their infinite growth and survival.

Highlights

Aberrant control of protein synthesis is a central driver of cellular transformation and tumor development
The underlying mechanism is unclear, this study proposed that engagement of these upstream ORF (uORF) is likely mediated by an alternative translation initiation factor, eIF2A, which is upregulated in many cancers
Using genome-wide ribosome profiling experiments in prostate cancer cells treated with mTOR ATP active site inhibitors, researchers have identified so-called TOP-like sequences such as the pyrimidine-rich translational element (PRTE) in proinvasive transcripts, including Y box–binding protein 1 (YBX1) and metastasis-associated 1 (MTA1) (Hsieh et al 2012)

Summary

Introduction

Aberrant control of protein synthesis is a central driver of cellular transformation and tumor development. The AMPK pathway is activated to suppress mTOR activity; whereas eIF2 kinases (PERK, HRI, PKR, and GCN2) phosphorylate the α subunit of eIF2, repressing global protein synthesis while increasing the translation of specific mRNAs that are critical to overcome the stress and promote cancer progression.

Results

Conclusion