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Updated: Jul 10, 2025
Spontaneous Murine Model of Anaplastic Thyroid Cancer
Published on: February 3, 2023
The m5 C methyltransferase NSUN2 promotes codon-dependent oncogenic translation by stabilising tRNA in anaplastic
Peng Li1,2,3, Wenlong Wang1,2, Ruixin Zhou1
1Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Background:
Translation dysregulation plays a crucial role in tumourigenesis and cancer progression. Oncogenic translation relies on the stability and availability of tRNAs for protein synthesis, making them potential targets for cancer therapy.
Methods:
This study performed immunohistochemistry analysis to assess NSUN2 levels in thyroid cancer. Furthermore, to elucidate the impact of NSUN2 on anaplastic thyroid cancer (ATC) malignancy, phenotypic assays were conducted. Drug inhibition and time-dependent plots were employed to analyse drug resistance. Liquid chromatography-mass spectrometry and bisulphite sequencing were used to investigate the m5 C methylation of tRNA at both global and single-base levels. Puromycin intake and high-frequency codon reporter assays verified the protein translation level. By combining mRNA and ribosome profiling, a series of downstream proteins and codon usage bias were identified. The acquired data were further validated by tRNA sequencing.
Results:
This study observed that the tRNA m5 C methyltransferase NSUN2 was up-regulated in ATC and is associated with dedifferentiation. Furthermore, NSUN2 knockdown repressed ATC formation, proliferation, invasion and migration both in vivo and in vitro. Moreover, NSUN2 repression enhanced the sensitivity of ATC to genotoxic drugs. Mechanically, NSUN2 catalyses tRNA structure-related m5 C modification, stabilising tRNA that maintains homeostasis and rapidly transports amino acids, particularly leucine. This stable tRNA has a substantially increased efficiency necessary to support a pro-cancer translation program including c-Myc, BCL2, RAB31, JUNB and TRAF2. Additionally, the NSUN2-mediated variations in m5C levels and different tRNA Leu iso-decoder families, partially contribute to a codon-dependent translation bias. Surprisingly, targeting NSUN2 disrupted the c-Myc to NSUN2 cycle in ATC.
Conclusions:
This research revealed that a pro-tumour m5C methyltransferase, dynamic tRNA stability regulation and downstream oncogenes, c-Myc, elicits a codon-dependent oncogenic translation network that enhances ATC growth and formation. Furthermore, it provides new opportunities for targeting translation reprogramming in cancer cells.
Insights
The tRNA methyltransferase NSUN2 promotes anaplastic thyroid cancer (ATC) by stabilizing tRNA, enhancing oncogenic translation. Targeting NSUN2 offers a new therapeutic strategy for ATC by disrupting this translation network.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Translation dysregulation is a key driver of tumor formation and progression.
- Transfer RNAs (tRNAs) are essential for protein synthesis and are implicated in oncogenic translation.
Purpose of the Study:
- To investigate the role of NSUN2 in anaplastic thyroid cancer (ATC) malignancy.
- To elucidate the impact of NSUN2-mediated tRNA modification on cancer progression and drug sensitivity.
Main Methods:
- Immunohistochemistry to assess NSUN2 levels in thyroid cancer.
- Phenotypic assays, drug inhibition studies, and time-dependent plots to analyze ATC malignancy and drug resistance.
- Liquid chromatography-mass spectrometry, bisulphite sequencing, and tRNA sequencing to investigate m5C methylation of tRNA.
- Puromycin intake, codon reporter assays, and ribosome profiling to assess protein translation and identify downstream targets.
Main Results:
- NSUN2 was upregulated in ATC and correlated with dedifferentiation.
- NSUN2 knockdown inhibited ATC formation, proliferation, invasion, and migration in vitro and in vivo.
- NSUN2 repression increased ATC sensitivity to genotoxic drugs.
- NSUN2 stabilizes tRNA, particularly for leucine, enhancing the translation of oncogenes like c-Myc, BCL2, RAB31, JUNB, and TRAF2.
- NSUN2-mediated m5C variations contributed to codon-dependent translation bias and disrupted the c-Myc to NSUN2 feedback loop.
Conclusions:
- NSUN2 acts as a pro-tumorigenic factor by regulating tRNA stability and promoting an oncogenic translation network involving c-Myc.
- Targeting NSUN2 represents a promising therapeutic strategy for anaplastic thyroid cancer by reprogramming translation.
- The study reveals a novel mechanism of oncogenic translation regulation in ATC.
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