New frontiers in translational control of the cancer genome

Abstract

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.

Figure 1. Oncogenic activation of mRNA translation

a | A central output of oncogenic MYC, RAS–MAPK, PI3K–AKT–mTOR and WNT–β-catenin signalling pathways is the aberrant activation of mRNA translation at the initiation and elongation steps. Translation initiation, the first step in this process, is considered the primary rate-limiting step of protein synthesis and typically proceeds in a ‘cap-dependent’ manner that relies on the ability of the eukaryotic translation initiation factor 4F (eIF4F) complex to bind to the 5′ 7-methylguanosine cap present on mature mRNAs. Oncogenic signalling promotes translation initiation predominantly through alterations in the eIF4F complex, which comprises the major cap-binding protein eIF4E, the scaffolding protein eIF4G and the helicase eIF4A. The eIF4F complex drives translation initiation through the ability of eIF4E to bind to the 5′ cap and interact with eIF4G, which recruits the 43S ribosomal pre-initiation complex (comprising a 40S ribosomal subunit, the eIF2–GTP–Met-tRNA_i^Met ternary complex, eIF3 and several additional accessory factors). Oncogenic signalling can hyperactivate eIF4E through enhanced transcription^,, through phosphorylation of eIF4E at serine 209 by the MAPK-interacting serine/threonine kinases (MNKs)^,, and through mTOR complex 1 (mTORC1)-dependent phosphorylation and inactivation of the eIF4E inhibitors eIF4E-binding proteins (4EBPs)^,,–,. Upon recruitment of the 43S complex to the 5′ untranslated region of mRNA, it scans in the 5′ to 3′ direction until reaching a start codon, a process facilitated by eIF4A helicase unwinding of secondary structures and promoted by ribosomal protein S6 kinase (S6K)-dependent stimulation of eIF4A activity through inhibition of programmed cell death protein 4 (PDCD4) and activation of eIF2B^,. Start codon recognition by the 43S complex is followed by GTP hydrolysis within the ternary complex and joining of the 60S ribosomal subunit to form a translationally competent ribosome. Translation can also be regulated at the elongation stage by oncogenic signalling, largely through S6K-dependent inhibition of eukaryotic translation elongation factor 2 (eEF2) kinase (eEF2K)^,,. Phosphorylation of eEF2K by S6K relieves its suppression of eEF2 (REF. 205), promoting the codon by codon translocation of the ribosome along the mRNA. Dashed arrows indicate indirect activation. b | Oncogenic activation of translation initiation and elongation supports tumorigenesis in part by driving selective changes in the translation of specific mRNA transcripts independently of alterations in transcript levels or global increases in protein synthesis. This selective translational control of specific mRNA transcripts underlies the acquisition and execution of distinct cancer cell behaviours central to the transformed phenotype, such as increased cell growth and proliferation, altered metabolism, enhanced angiogenesis, proper reactive oxygen species (ROS) control, immune cell recruitment, and invasion and metastasis^,. CCL, C-C motif chemokine ligand; CCND3, cyclin D3; FTH1, ferritin heavy polypeptide 1; GCLC, glutamate–cysteine ligase catalytic subunit; MTA1, metastasis-associated 1; PRPS2, phosphoribosyl pyrophosphate synthetase 2; RAPTOR, regulatory associated protein of mTORC1; VEGFA, vascular endothelial growth factor A; YB1, Y-box binding protein 1.

Figure 2. mRNA regulatory elements direct specialized translation of the oncogenic programme

Structural and sequence-specific regulatory elements underlie the code for selective control of the translation of specific pro-tumorigenic mRNAs. a | General secondary structure in the 5′ untranslated region (5′UTR) can steer selective translation of mRNAs, such as the metabolic enzyme ornithine decarboxylase (ODC), by conferring enhanced sensitivity to eukaryotic initiation factor 4F (eIF4F) complex formation, which promotes unwinding of these structures through the eIF4A helicase. b | Likewise, mRNAs with G-quadruplexes in their 5′UTR, such as the super-enhancer-associated transcription factor ETS1, selectively require eIF4A helicase activity for their translation. c | Transcripts containing a structural element called an internal ribosome entry site (IRES), such as the anti-apoptotic BCL2 (REF. 50), can be selectively translated in a cap-independent manner by directly recruiting the ribosome to the 5′UTR, frequently with the aid of IRES trans-acting factors (ITAFs). d | Many structural elements confer translational specificity through interactions with distinct RNA-binding proteins (RBPs). For example, the epithelial–mesenchymal transition regulator disabled homologue 2 (DAB2) contains a 3′UTR transforming growth factor-β (TGFβ)-activated translation (BAT) element that recruits RBPs to form a complex that blocks translation elongation^,. e | Structural elements in the 5′UTR have even been shown to interact with eIF3, which non-canonically binds RNA in a manner dependent on the presence of distinct stem–loops. For example, direct interaction of eIF3 with a stem–loop in the 5′UTR of the mRNA encoding the mitotic regulator JUN promotes its translation. f | One of the shortest sequence-specific elements in the 5′UTR is an alternative translation start site, typically comprising an upstream AUG (uAUG) or, more rarely, a non-AUG codon. These upstream start codons are in-frame with the primary open reading frame (ORF) and can drive the expression of protein isoforms with novel functions, such as the long form of the tumour suppressor PTEN (PTEN-long), the translation of which starts from an upstream CUG codon. g | Upstream ORFs (uORFs) are discontiguous from the primary ORF and typically act to inhibit translation, as has been shown for the growth factor receptor HER2 (REF. 74). However, under certain conditions uORFs can act to promote translation (see FIG. 4). h | MicroRNAs (miRNAs) recognize complementary sequences in target mRNAs and guide transcript-specific translational repression as part of the miRNA-induced silencing complex (miRISC), as has been shown for let-7 regulation of the RAS oncogenes. Cancer cells can reduce their 3′UTR length through alternative cleavage and polyadenylation (APA) to avoid miRNA-mediated regulation. i | Many RBPs recognize sequence-specific RBP-binding domains (RBDs) in the 3′UTR to regulate transcript-specific translation, as has been shown for the RBP Musashi homologue 2-induced translation of the self-renewal factor Ikaros family zinc finger protein 2 (IKZF2). j | There is recent and growing appreciation of the presence of numerous sequence-specific elements in the 5′UTR, including the translation inhibitory element (TIE), pyrimidine-rich translational element (PRTE)^, and cytosine-enriched regulator of translation (CERT), all of which can direct selective cap-dependent translation of distinct transcripts that influence tumour development and progression. Although the underlying molecular mechanisms by which these elements exert translational control remains to be elucidated, they may function in part by recruiting specific trans-acting factors (light blue circles labelled ‘?’) that interact directly or indirectly with the translation initiation complex. FTH1, ferritin heavy polypeptide 1; PRPS2, phosphoribosyl pyrophosphate synthetase 2.

Figure 3. Codon usage: a new layer of control in translation of the cancer genome

Oncogenic signalling can drive changes in the transcription of tRNA genes and their modifications (denoted here as red asterisks in the anticodon loop), leading to the expression of a specific repertoire of tRNAs in the cancer cell. This can in turn support the translation of pro-tumorigenic mRNAs based on their codon usage bias, whereby mRNAs with codons better matched to the tRNA pool (depicted here by matched codon and tRNA colour) are more likely to be translated. For example, the cancer cell tRNA pool is well matched to the codon usage of transcripts involved in cellular proliferation, such as cell cycle genes, but not to those mRNAs involved in differentiation, such as pattern specification genes^,. Pol, RNA polymerase.

Figure 4. Translational responses and cancer cell adaptation to tumour-associated stress

The ability of cancer cells to adapt to stresses encountered during tumorigenesis is fundamental for tumour growth and survival. One of the major cellular responses to stress conditions is global inhibition of protein synthesis, which acts to conserve energy and prevent the accumulation of damaged proteins. This is mediated largely at the level of translation initiation through decreases in eukaryotic initiation factor 4E (eIF4E) activity downstream of mTOR–eIF4E-binding protein (4EBP) signalling and inhibition of eIF2A by the eIF2A kinase family, which includes PRKR-like endoplasmic reticulum (ER) kinase (PERK) and general control non-derepressible 2 (GCN2). Stress conditions can also block translation elongation through AMP-activated protein kinase (AMPK)-dependent activation of eukaryotic translation elongation factor 2 (eEF2) kinase (eEF2K), which inhibits eEF2 (REF. 11). Although oncogenic signalling frequently suppresses the AMPK–eEF2K pathway, cancer cells selectively reactivate this pathway to promote survival during nutrient deprivation. Cancer cells can also adapt to stress by increasing the translation of selective mRNA transcripts that promote cell survival and resolve stress conditions. This adaptive stress response is driven in part by internal ribosome entry site (IRES)- and upstream open reading frame (uORF)-dependent translational mechanisms that can be maintained or even favoured under conditions in which global protein synthesis is inhibited and can promote the translation of pro-survival genes, such as BCL2 (REF. 50) and X-linked inhibitor of apoptosis protein (XIAP), and stress response genes such as excision repair cross-complementation group 5 (ERCC5). Likewise, it has been revealed that under hypoxic conditions that inhibit global protein synthesis the eIF4E homologue 4EHP can promote the translation of select mRNAs involved in the adaptive response to hypoxia, including epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor-α (PDGFRA). Recently, exciting new studies have revealed that even eIF4E can act to promote the adaptive response to stress, for example, through enhanced translation of reactive oxygen species (ROS) regulators such as ferritin heavy polypeptide 1 (encoded by FTH1) and glutamate–cysteine ligase catalytic subunit (encoded by GCLC). As cancer cells do not always globally downregulate protein synthesis in response to stress, this new-found role for eIF4E may be especially relevant for tumorigenesis.