Related Experiment Video
Updated: Sep 10, 2025
Author Spotlight: Exploring Salidroside's Molecular Mechanisms in Breast Cancer Treatment
Published on: June 9, 2023
NSUN2-tRNAVal-CAC-axis-regulated codon-biased translation drives triple-negative breast cancer glycolysis and
Wenlong Wang1,2,3, Ying Ding4, Haixi Zhao5
1Department of Breast Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China.
Background:
Epitranscriptomic data indicate that aberrant tRNA modifications in malignant diseases can promote tumor growth by facilitating oncogene translation. NSUN2, a 5-methylcytosine (m5C) methyltransferase of tRNA, is elevated in an array of solid cancers, including triple-negative breast cancer (TNBC). However, it remains unclear how NSUN2 drives aggressive behavior and if NSUN2 could be an effective therapeutic target for TNBC.
Methods:
Functional experiments, including RNA interference, lentivirus transduction, and in vivo xenograft models, were conducted to evaluate the role of NSUN2 in TNBC cell proliferation, metastasis, and chemoresistance. Ribosome sequencing (Ribo-seq), tRNA m5C bisulfite sequencing, and codon usage bias analysis were employed to explore the translational mechanisms underlying NSUN2-mediated tRNA modifications. Glycolysis assays and molecular docking were used to investigate metabolic reprogramming and protein interactions.
Results:
NSUN2 was significantly upregulated in TNBC and correlated with poor patient prognosis. Mechanistically, NSUN2 mediates m5C modification of tRNAVal-CAC, enhancing the codon-frequency-dependent translation of key glycolysis-related genes, including ALDH3A2, ALDH7A1, HK1, and PFKM. Depletion of NSUN2 disrupted tRNAVal-CAC m5C modification, impairing the translation of these metabolic enzymes and suppressing glycolysis, which ultimately inhibited TNBC cell proliferation, migration, and invasion both in vitro and in vivo. Furthermore, NSUN2 overexpression conferred resistance to docetaxel, while its inhibition sensitized TNBC cells to docetaxel treatment. Clinically, elevated expression levels of NSUN2 and glycolysis-related genes were observed in docetaxel-resistant TNBC tissues, further supporting the role of NSUN2 in chemoresistance.
Conclusions:
This study identifies NSUN2 as a critical regulator of TNBC progression through tRNAVal-CAC m5C modification and codon-biased translation of glycolysis-related mRNAs. Our findings reveal a novel NSUN2-tRNAVal-CAC axis that orchestrates metabolic reprogramming and translational control in TNBC, offering a promising prognostic biomarker and therapeutic target.
Insights
NSUN2 elevates glycolysis in triple-negative breast cancer (TNBC) by modifying tRNA, promoting tumor growth and chemoresistance. Inhibiting NSUN2 offers a potential therapeutic strategy for TNBC.
Area of Science:
- Oncology
- Molecular Biology
- Epitranscriptomics
Background:
- Aberrant tRNA modifications in cancer can enhance oncogene translation and tumor growth.
- NSUN2 (5-methylcytosine methyltransferase) is upregulated in various solid cancers, including triple-negative breast cancer (TNBC).
- The precise role of NSUN2 in TNBC progression and its potential as a therapeutic target remain largely unexplored.
Purpose of the Study:
- To elucidate the role of NSUN2 in TNBC pathogenesis and aggressive behaviors.
- To investigate the underlying molecular mechanisms, particularly tRNA modifications and translational control.
- To evaluate NSUN2 as a potential therapeutic target for TNBC.
Main Methods:
- Functional assays (RNA interference, lentivirus transduction, xenografts) to assess NSUN2's impact on TNBC.
- Ribosome sequencing (Ribo-seq) and tRNA m5C bisulfite sequencing to analyze translational and modification patterns.
- Glycolysis assays and molecular docking to explore metabolic reprogramming and protein interactions.
Main Results:
- NSUN2 upregulation in TNBC correlates with poor prognosis.
- NSUN2 mediates m5C modification of tRNAVal-CAC, enhancing translation of glycolysis genes (ALDH3A2, ALDH7A1, HK1, PFKM).
- NSUN2 depletion suppresses glycolysis, proliferation, and metastasis; NSUN2 inhibition sensitizes TNBC to docetaxel, with elevated NSUN2/glycolysis genes in resistant tissues.
Conclusions:
- NSUN2 is a critical regulator of TNBC progression via tRNAVal-CAC m5C modification and codon-biased translation of glycolysis mRNAs.
- A novel NSUN2-tRNAVal-CAC axis controls metabolic reprogramming and translation in TNBC.
- NSUN2 serves as a promising prognostic biomarker and therapeutic target for TNBC.
Related Concept Videos
02:55The Nucleolus
01:31Translation
Translation Produces the Building Blocks of Life
Proteins are...
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
02:53Adaptive Mechanisms in Cancer Cells
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
02:28Leaky Scanning
02:07Tumor Progression
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...