Translation initiation and its relevance in colorectal cancer

Abstract

Protein synthesis is one of the most essential processes in every kingdom of life, and its dysregulation is a known driving force in cancer development. Multiple signaling pathways converge on the translation initiation machinery, and this plays a crucial role in regulating differential gene expression. In colorectal cancer, dysregulation of initiation results in translational reprogramming, which promotes the selective translation of mRNAs required for many oncogenic processes. The majority of upstream mutations found in colorectal cancer, including alterations in the WNT, MAPK, and PI3K\AKT pathways, have been demonstrated to play a significant role in translational reprogramming. Many translation initiation factors are also known to be dysregulated, resulting in translational reprogramming during tumor initiation and/or maintenance. In this review, we outline the role of translational reprogramming that occurs during colorectal cancer development and progression and highlight some of the most critical factors affecting the etiology of this disease.

Keywords: RNA translation; colorectal cancer; protein synthesis; translation initiation; translational control.

Fig. 1

Eukaryotic translation initiation. Schematic representation of eukaryotic translation initiation, including cap‐dependent and cap‐independent translation initiation. The primary mode of initiation is cap‐dependent translation; however, this mechanism can be suppressed in response to a variety of pathophysiological stressors. Cap‐dependent initiation involves the formation of the 43S PIC, followed by the recruitment of the mRNA template facilitated by the eIF4F complex. Once activated, the 43S PIC scans along the 5’UTR of the transcript until the initiator codon (AUG) is recognized, resulting in the release of various eIFs and the formation of the translation competent 80S ribosome. In response to specific stressors, the cell is able to adapt its gene expression pattern through reprogramming of the protein synthesis, using the cap‐independent translation initiation such as IRES‐mediated initiation. These structured mRNA sequences downstream of the 5’UTR m⁷G‐cap can regulate cap‐independent translation initiation via various mechanisms using both the canonical eIFs and IRES trans‐acting factors. The exact mechanisms and detailed explanations of the translation initiation machinery are provided in the text. Created with BioRender.com.

Fig. 2

Translational control in CRC. Schematic representation of the translational control in CRC, including the upstream regulatory pathways and the translation initiation machinery. Factors contributing to the translational reprogramming in CRC are mutations and alterations found in the APC gene, in genes involved in RAS/MAPK signaling, including KRAS and BRAF, and in PI3K/AKT signaling, via alterations in PTEN and PI3K (marked in red). In CRC, the translational reprogramming is mainly regulated via the function and activation of the central regulators mTORC1 and c‐Myc. Besides these alterations found in the upstream signaling pathways, the altered expression and activity of numerous eIFs as well as the upregulation of components for ribosomal biogenesis and factors controlling translation in response to stress, are shown to dysregulate the translation initiation machinery in CRC. Positive regulators of the canonical translation initiation machinery are shown in green, while the negative regulators of this process are shown in blue and the individual translation initiation factors are shown in purple. Detailed explanations and descriptions about the translational control and its reprogramming in CRC are provided in the text. Created with BioRender.com.

Fig. 3

The function of transcription factor c‐Myc in translational control. Schematic representation of the function of c‐Myc during translational reprogramming in CRC. The loss of upstream key regulator APC increases the global translation rates via the overexpression of c‐Myc, through the constitutive accumulation of β‐cat. The constitutive overexpression of c‐Myc stimulates the transcription and activation of major downstream effectors involved in the oncogenic translation initiation machinery. c‐Myc overexpression in CRC can lead to an upregulation of ribosome biogenesis and is implicated in cellular responses to stress via regulating the activity of stress‐related kinases GCN2 and PERK and that of the eIF2α/eIF2B complex, driving cap‐independent translation initiation. Detailed explanations and descriptions about the function of c‐Myc in translational control and its reprogramming in CRC are provided in the text. Created with BioRender.com.

Fig. 4

The upstream regulatory pathways controlling translational reprogramming in CRC. Schematic representation of the key upstream regulatory pathways regulating translational control in CRC. mTORC1 lies at the nexus of the major signaling pathways driving translational control, and its activation can be controlled via upstream signaling pathways RAS/MAPK and PI3K/AKT. In CRC, oncogenic signaling via mutations and alterations in these pathways can promote translational reprogramming, predominantly through the altered function of mTORC1 but also via the RAS/MAPK pathway directly. Factors contributing to such hyperactivated mTORC1 signaling are mutations and alterations found in the APC gene, in genes involved in RAS/MAPK signaling, including KRAS and BRAF, and in PI3K/AKT signaling, via alterations in PTEN and PI3K. Detailed explanations and abbreviations about the function of the upstream regulatory pathways in translational control and its reprogramming in CRC are provided in the text. Created with BioRender.com.