The impact of tRNA modifications on translation in cancer: identifying novel therapeutic avenues

Abstract

Recent advancements have illuminated the critical role of RNA modifications in post-transcriptional regulation, shaping the landscape of gene expression. This review explores how tRNA modifications emerge as critical players, fine-tuning functionalities that not only maintain the fidelity of protein synthesis but also dictate gene expression and translation profiles. Highlighting their dysregulation as a common denominator in various cancers, we systematically investigate the intersection of both cytosolic and mitochondrial tRNA modifications with cancer biology. These modifications impact key processes such as cell proliferation, tumorigenesis, migration, metastasis, bioenergetics and the modulation of the tumor immune microenvironment. The recurrence of altered tRNA modification patterns across different cancer types underscores their significance in cancer development, proposing them as potential biomarkers and as actionable targets to disrupt tumorigenic processes, offering new avenues for precision medicine in the battle against cancer.

Graphical Abstract

Figure 1.

Overview of cancer-regulatory mechanisms affected by m⁷G methylation. The chart shows the cellular pathways affected in each tumor when METTL1 is deleted or silenced, via tRNA hypomethylation and/or tRNA fragments. Proliferation and migration are reduced in all cases. In all cancer types, METTL1 is overexpressed: hepatocellular carcinoma (HCC), intrahepatic cholangiocellular carcinoma (ICC), head and neck squamous cell carcinoma (HNSCC), prostate cancer (PCa), esophageal squamous cell carcinoma (ESCC), bladder cancer (BCa), nasopharyngeal carcinoma (NPC) and osteosarcoma (OS). ICB therapy: immune checkpoint blockade therapy.

Figure 2.

Cytosolic tRNA modifications impacting tumoral processes. Epitranscriptomic marks deposited in cytosolic tRNAs have been implicated in various cancerous processes, including proliferation (green), migration and metastasis (blue), and therapy resistance (pink). These consequences arise from diverse molecular alterations such as impaired translation or codon bias (orange), the biogenesis of tRFs (purple), tRNA stability (yellow) or a still unknown mechanism (gray). The illustration progresses from the outermost to the innermost layers, detailing the tRNA isotype that undergoes modification—if no tRNA isotype is indicated, several tRNA isotypes are involved—; the associated tumor type; the enzyme responsible for each mark, and whether it is up- or down-regulated (indicated by gray thick arrows); the mark; and the position of the mark. Solid tumors encompass all the solid tumors specified in this figure. Modifications located on the anticodon loop, D arm and acceptor stem are highlighted to indicate their involvement in amino acid recognition, codon usage and tRNA stability. Meanwhile, those modifications situated at the variable loop are indicated as being involved in tRF biogenesis. Glioblastoma (GBM), ovarian carcinoma (OC), cervical carcinoma (CC), osteosarcoma (OS), esophageal carcinoma (ESCC), lung adenocarcinoma (LUAD), melanoma (M), gallbladder cancer (GBC), squamous cell carcinoma (SCC), acute lymphoblastic leukemia (ALL), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), hepatocellular carcinoma (HCC), pancreatic cancer (PaC), breast cancer (BC) and renal cell carcinoma (RCC).

Figure 3.

Mitochondrial tRNA modifications. The modifications and the corresponding writers are depicted in the tRNA backbone in different colors according to the oncogenic features in which they are involved, i.e. proliferation (green) and migration and metastasis (blue), as well as mitochondrial properties, i.e. mitochondrial protein synthesis (orange), altered bioenergetics (yellow) and OXPHOS activity (purple). The illustration progresses from the outermost to the innermost layers, providing details on the associated tumor types, the enzyme responsible for each mark and whether it is up- or down-regulated (indicated by arrows). The information includes the specific mark, along with the position where the enzyme catalyzes the mark. The category of solid tumors includes glioblastoma (GBM), endometrial carcinoma (EC), ovarian carcinoma (OC), cervical carcinoma (CC), lung adenocarcinoma (LUAD), colorectal cancer (CRC), breast cancer (BC), diffuse large B cell carcinoma (DLBC), low-grade glioma (LGG), lung squamous cell carcinoma (LUSC), pancreatic cancer (PaC), stomach adenocarcinoma (STAD), thyroid carcinoma (THYM) and squamous cell carcinoma (SCC).