Deregulation in different steps of translational control is an emerging mechanism for cancer formation. One example of an oncogene with a direct role in control of translation is the Myc ...transcription factor. Myc directly increases protein synthesis rates by controlling the expression of multiple components of the protein synthetic machinery, including ribosomal proteins and initiation factors of translation, Pol III and rDNA. However, the contribution of Myc-dependent increases in protein synthesis toward the multistep process leading to cancer has remained unknown. Recent evidence strongly suggests that Myc oncogenic signaling may monopolize the translational machinery to elicit cooperative effects on cell growth, cell cycle progression, and genome instability as a mechanism for cancer initiation. Moreover, new genetic tools to restore aberrant increases in protein synthesis control are now available, which should enable the dissection of important mechanisms in cancer that rely on the translational machinery.
The past several years have seen dramatic leaps in our understanding of how gene expression is rewired at the translation level during tumorigenesis to support the transformed phenotype. This work ...has been driven by an explosion in technological advances and is revealing previously unimagined regulatory mechanisms that dictate functional expression of the cancer genome. In this Review we discuss emerging trends and exciting new discoveries that reveal how this translational circuitry contributes to specific aspects of tumorigenesis and cancer cell function, with a particular focus on recent insights into the role of translational control in the adaptive response to oncogenic stress conditions.
Elevated protein synthesis is an important feature of many cancer cells and often arises as a consequence of increased signaling flux channeled to eukaryotic initiation factor 4F (eIF4F), the key ...regulator of the mRNA-ribosome recruitment phase of translation initiation. In many cellular and preclinical models of cancer, eIF4F deregulation results in changes in translational efficiency of specific mRNA classes. Importantly, many of these mRNAs code for proteins that potently regulate critical cellular processes, such as cell growth and proliferation, enhanced cell survival and cell migration that ultimately impinge on several hallmarks of cancer, including increased angiogenesis, deregulated growth control, enhanced cellular survival, epithelial-to-mesenchymal transition, invasion, and metastasis. By being positioned as the molecular nexus downstream of key oncogenic signaling pathways (e.g., Ras, PI3K/AKT/TOR, and MYC), eIF4F serves as a direct link between important steps in cancer development and translation initiation. Identification of mRNAs particularly responsive to elevated eIF4F activity that typifies tumorigenesis underscores the critical role of eIF4F in cancer and raises the exciting possibility of developing new-in-class small molecules targeting translation initiation as antineoplastic agents.
Key signaling pathways (such as phosphoinositide 3-kinase, Myc, and RAS) act as sensors of energy, stress, and nutrient availability and integrate these inputs to directly control ribosome production ...and gene expression at the translational level. This activity is normally directly coupled to cell growth, division, and survival. However, it remains poorly understood the extent to which changes in ribosome number and nucleolar integrity downstream of these key signaling pathways contribute to their oncogenic activity. Emerging studies provide interesting insight into how deregulations in RNA polymerase I activity may lead to tumorigenesis and suggest that new drugs targeting ribosomal DNA transcription may hold great promise for the treatment of cancer.
Cancer cells develop mechanisms to escape immunosurveillance, among which modulating the expression of immune suppressive messenger RNAs is most well-documented. However, how this is molecularly ...achieved remains largely unresolved. Here, we develop an in vivo mouse model of liver cancer to study oncogene cooperation in immunosurveillance. We show that MYC overexpression (MYC
) synergizes with KRAS
to induce an aggressive liver tumor leading to metastasis formation and reduced mouse survival compared with KRAS
alone. Genome-wide ribosomal footprinting of MYC
;KRAS
tumors compared with KRAS
revealed potential alterations in translation of mRNAs, including programmed-death-ligand 1 (PD-L1). Further analysis revealed that PD-L1 translation is repressed in KRAS
tumors by functional, non-canonical upstream open reading frames in its 5' untranslated region, which is bypassed in MYC
;KRAS
tumors to evade immune attack. We show that this mechanism of PD-L1 translational upregulation was effectively targeted by a potent, clinical compound that inhibits eIF4E phosphorylation, eFT508, which reverses the aggressive and metastatic characteristics of MYC
;KRAS
tumors. Together, these studies reveal how immune-checkpoint proteins are manipulated by distinct oncogenes at the level of mRNA translation, which can be exploited for new immunotherapies.
Alterations in transcript‐specific translation are emerging as a driver of cellular transformation and cancer etiology. A new study provides evidence for enhanced codon‐dependent translation of ...hypoxia‐inducible factor 1α in promoting glycolytic metabolism and drug resistance in melanoma cells. This specialized translation reprogramming relies, in part, on mTORC2‐mediated phosphorylation of enzymes modifying the wobble position of the transfer RNA anticodon.
A new study shows that codon‐dependent translation regulation of HIF1α couples glycolytic metabolism to drug resistance in skin cancer.
Recent advances in understanding the role of eukaryotic translation initiator factor 4E (eIF4E) in tumorigenesis and cancer progression have generated significant interest in therapeutic agents that ...indirectly or directly target aberrant activation of eIF4E in cancer. Here, we address the general function of eIF4E in translation initiation and cancer, present evidence supporting its role in cancer initiation and progression, and highlight emerging therapeutics that efficiently target hyperactivated eIF4E. In doing so, we also highlight the major differences between these therapeutics that may influence their mechanism of action.
Small nucleolar RNAs (snoRNAs) are a diverse group of non-coding RNAs that direct chemical modifications at specific residues on other RNA molecules, primarily on ribosomal RNA (rRNA). SnoRNAs are ...altered in several cancers; however, their role in cell homeostasis as well as in cellular transformation remains poorly explored. Here, we show that specific subsets of snoRNAs are differentially regulated during the earliest cellular response to oncogenic RAS
expression. We describe a novel function for one H/ACA snoRNA,
, which guides two pseudouridine modifications within the small ribosomal subunit, in RAS-induced senescence in vivo. We find that in mouse models, loss of
cooperates with RAS
to promote the development of liver cancer that closely resembles human steatohepatitic hepatocellular carcinoma (HCC). From a clinical perspective, we further show that human HCCs with low
expression display increased lipid content and are associated with poor patient survival. We next asked whether ribosomes lacking
-guided pseudouridine modifications on 18S rRNA have alterations in their biophysical properties. Single-molecule Fluorescence Resonance Energy Transfer (FRET) analyses revealed that these ribosomes exhibit perturbations in aminoacyl-transfer RNA (aa-tRNA) selection and altered pre-translocation ribosome complex dynamics. Furthermore, we find that HCC cells lacking
-guided pseudouridine modifications have increased translational miscoding and stop codon readthrough frequencies. These findings highlight a role for specific snoRNAs in safeguarding against oncogenic insult and demonstrate a functional link between H/ACA snoRNAs regulated by RAS and the biophysical properties of ribosomes in cancer.
Hyperconnectivity of neuronal circuits due to increased synaptic protein synthesis is thought to cause autism spectrum disorders (ASDs). The mammalian target of rapamycin (mTOR) is strongly ...implicated in ASDs by means of upstream signalling; however, downstream regulatory mechanisms are ill-defined. Here we show that knockout of the eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2)-an eIF4E repressor downstream of mTOR-or eIF4E overexpression leads to increased translation of neuroligins, which are postsynaptic proteins that are causally linked to ASDs. Mice that have the gene encoding 4E-BP2 (Eif4ebp2) knocked out exhibit an increased ratio of excitatory to inhibitory synaptic inputs and autistic-like behaviours (that is, social interaction deficits, altered communication and repetitive/stereotyped behaviours). Pharmacological inhibition of eIF4E activity or normalization of neuroligin 1, but not neuroligin 2, protein levels restores the normal excitation/inhibition ratio and rectifies the social behaviour deficits. Thus, translational control by eIF4E regulates the synthesis of neuroligins, maintaining the excitation-to-inhibition balance, and its dysregulation engenders ASD-like phenotypes.
Cancer cells must integrate multiple biosynthetic demands to drive indefinite proliferation. How these key cellular processes, such as metabolism and protein synthesis, crosstalk to fuel cancer cell ...growth is unknown. Here, we uncover the mechanism by which the Myc oncogene coordinates the production of the two most abundant classes of cellular macromolecules, proteins, and nucleic acids in cancer cells. We find that a single rate-limiting enzyme, phosphoribosyl-pyrophosphate synthetase 2 (PRPS2), promotes increased nucleotide biosynthesis in Myc-transformed cells. Remarkably, Prps2 couples protein and nucleotide biosynthesis through a specialized cis-regulatory element within the Prps2 5′ UTR, which is controlled by the oncogene and translation initiation factor eIF4E downstream Myc activation. We demonstrate with a Prps2 knockout mouse that the nexus between protein and nucleotide biosynthesis controlled by PRPS2 is crucial for Myc-driven tumorigenesis. Together, these studies identify a translationally anchored anabolic circuit critical for cancer cell survival and an unexpected vulnerability for “undruggable” oncogenes, such as Myc.
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•Protein synthesis and nucleotide metabolism are coupled downstream of Myc•Translational control of Prps2 integrates nucleotide metabolism and protein synthesis•Loss of function of PRPS2, but not of PRPS1, is synthetic lethal upon Myc overexpression•Prps2 is dispensable for normal physiology but is essential for Myc-driven lymphoma
Elevated translation of a nucleotide biosynthesis enzyme proves to be a key nexus coordinating protein and nucleic acid synthesis in MYC-transformed cells, thereby revealing a vulnerability for “undruggable” oncogenes.
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