August 25th, 2024
Recent Publications Harnessing the Power of Translatomics
Every week we provide a digest of a small number of recent interesting papers in the field of translatomics.
In this week’s Sunday papers, Wu et al. highlighted that FOXA1 affects TGF-β1-induced epithelial-mesenchymal transition in gallbladder carcinoma. Huang et al. showed that tRNA-derived fragments play a role in regulating breast cancer progression. Li et al. used bioorthogonal labelling to demonstrate the biological significance of prenyl modifications that enhance interactions with cell membranes and play critical roles in cellular processes.
TGF-β1 facilitates gallbladder carcinoma metastasis by regulating FOXA1 translation efficiency through m⁶A modification
Cell Death & Disease, 2024
Wu, Z., Ke, Q., Jiang, L., Hong, H., Pan, W., Chen, W., Abudukeremu, X., She, F. and Chen, Y.
Gallbladder carcinoma (GBC) accounts for nearly two-thirds of biliary system tumours, in addition to having a poor prognosis due to its metastatic nature. Epithelial-mesenchymal transition (EMT) is crucial for GBC metastasis, with TGF-β1 being a key EMT regulator. TGF-β1 is upregulated in GBC, promoting EMT, but its mechanisms are unclear. FOXA1, a “pioneer factor,” influences EMT and is hypothesized to play a role in TGF-β1-induced EMT in GBC. This study aimed to explore how TGF-β1 affects FOXA1 expression via m⁶A modification. By investigating the molecular pathways and conducting in vivo experiments and tissue analysis, the study highlighted FOXA1’s role in GBC, offering insights for targeted therapies.
The study found that TGF-β1 inhibits FOXA1 protein expression in GBC by promoting m⁶A modification in the coding sequence (CDS) region of FOXA1 mRNA, reducing its translation efficiency. Polysome profiling revealed that TGF-β1 shifts FOXA1 mRNA away from translationally active polysomes. FOXA1 inhibits TGF-β1-induced migration and EMT in GBC cells, and its high expression correlates with better patient survival. These findings highlight TGF-β1’s role in GBC metastasis and suggest FOXA1 as a potential therapeutic target.
Polysome profiling was crucial in showing how TGF-β1 affects the translation of FOXA1 mRNA. Understanding TGF-β1’s regulation of FOXA1 via m⁶A modification opens new possibilities for treating GBC. Targeting these pathways could inhibit metastasis and improve patient outcomes. By focusing on enhancing FOXA1 expression or blocking its suppression by TGF-β1, new therapies could potentially prevent tumour spread.
Downregulation of tRF-Cys-GCA-029 by hyperglycemia promotes tumorigenesis and glycolysis of diabetic breast cancer through upregulating PRKCG translation
Breast Cancer Research, 2024
Huang, Y., Chen, C., Liu, Y., Tan, B., Xiang, Q., Chen, Q., Wang, Y., Yang, W., He, J., Zhou, D. and Wang, Y.
Breast cancer (BC) and diabetes mellitus (DM) significantly impact global health, with BC becoming the most common cancer worldwide in 2020. DM affects up to one-third of BC patients, leading to a higher mortality risk for those with both conditions compared to those with only BC. Despite this, the molecular mechanisms of the BC-DM interplay remain underexplored. This study aims to investigate these mechanisms, focusing on tRNA-derived fragments (tRFs), particularly tRF-Cys-GCA-029, and its role in BC-DM malignancy and glycolysis metabolism.
The study discovered that tRF-Cys-GCA-029 is significantly downregulated in BC-DM tissues and under hyperglycaemia in BC cells, promoting BC cell proliferation, migration, and glycolysis, as indicated by increased lactate/pyruvate production and ECAR levels. Injecting tRF-Cys-GCA-029 mimics into diabetic mice significantly suppressed BC tumour growth. Polysome profiling and RNA sequencing revealed that tRF-Cys-GCA-029 interacts with PRKCG by binding to its mRNA coding sequence, regulating transcription, and modifying its translation, thus influencing BC cell malignancy and glycolysis.
These findings suggest that tRF-Cys-GCA-029 plays a crucial role in BC-DM progression by reprogramming glycolysis metabolism and propose targeting the tRF-Cys-GCA-029-PRKCG axis as a potential targeted therapeutic approach against BC-DM.
Bioorthogonal labeling and profiling of N⁶-isopentenyladenosine (i⁶A) modified RNA
Nucleic Acids Research, 2024
Li, Y., Zhou, H., Chen, S., Li, Y., Guo, Y., Chen, X., Wang, S., Wang, L., Gan, Y., Zhang, S. and Zheng, Y.Y.
RNAs exhibit versatile roles in cellular functions and have ample potential for therapeutic use. Despite significant advancements in RNA research, understanding the complexity of RNA biology, especially the biological significance of prenyl-modified RNAs, remains challenging. Prenyl modifications involve the addition of hydrophobic prenyl groups, derived from isoprene units to biomolecules like proteins or RNAs. These modifications enhance interactions with cell membranes, affecting function, localization, and stability, and play critical roles in cellular processes, gene expression, and various diseases. This study focuses on developing new molecular tools to investigate RNA structures and functions, specifically targeting prenyl modifications.
Researchers employed Ene-ligation bioorthogonal chemistry and PTAD-based fluorescence probes to directly label i⁶A-containing RNAs in vitro. By synthesizing an i⁶A triphosphate building block, they demonstrated its incorporation by eukaryotic RNA polymerase, allowing for adjustable i⁶A concentrations and direct labelling with fluorescent dyes. This enabled the study of i⁶A functions and RNA tracking. Additionally, the iodine-mediated cyclization and reverse transcription sequencing (IMCRT tRNA-seq) method was developed to profile i⁶A residues in cellular tRNAs with single nucleotide precision. Using this method, researchers accurately identified tRNAs with i⁶A37 and observed changes in i⁶A levels under stress conditions, facilitating the study of i⁶A’s biological roles.
This study introduced innovative methods for precise labelling and detection of i⁶A-modified RNAs, including PTAD-baseed fluorescence probes and IMCRT tRNA-seq. These tools enable detailed RNA modification analysis, enhancing understanding of RNA roles in cellular processes and diseases, and paving the way for advanced RNA-based therapeutic developments.