TRMT6-mediated tRNA m¹A modification acts as a translational checkpoint of histone synthesis and facilitates colorectal cancer progression

En-Wei Tao^#^{1

2

3

4

5}, Ye Wang^#^{1

2

3

4

5}, Juan Tan^#^{1

2

3

4

5}, Yan Chen^{1

2

3

4

5}, Tian-Yue Sun^{1

2

3

4

5}, Yu Hao^{1

2

3

4

5}, Hao-Lian Wang^{1

2

3

4

5}, Qianqian Liu^{1

2

3

4

5}, Yun-Qian Wang^{1

2

3

4

5}, Linna Fu^{1

2

3

4

5}, Zhi-Qing Zhan^{1

2

3

4

5}, Haoyan Chen^{1

2

3

4

5}, Jie Hong^{1

2

3

4

5}, Qin-Yan Gao^{6

7

8

9

10}, Jing-Yuan Fang^{11

12

13

14

15}, Ying-Xuan Chen^{16

17

18

19

20}

Affiliations

¹ Division of Gastroenterology and Hepatology, Shanghai Jiao Tong University, Shanghai, China.
² Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China.
³ NHC Key Laboratory of Digestive Diseases, Shanghai Jiao Tong University, Shanghai, China.
⁴ State Key Laboratory for Oncogenes and Related Genes, Shanghai Jiao Tong University, Shanghai, China.
⁵ Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁶ Division of Gastroenterology and Hepatology, Shanghai Jiao Tong University, Shanghai, China. gaoqinyan@sohu.com.
⁷ Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China. gaoqinyan@sohu.com.
⁸ NHC Key Laboratory of Digestive Diseases, Shanghai Jiao Tong University, Shanghai, China. gaoqinyan@sohu.com.
⁹ State Key Laboratory for Oncogenes and Related Genes, Shanghai Jiao Tong University, Shanghai, China. gaoqinyan@sohu.com.
¹⁰ Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. gaoqinyan@sohu.com.
¹¹ Division of Gastroenterology and Hepatology, Shanghai Jiao Tong University, Shanghai, China. jingyuanfang@sjtu.edu.cn.
¹² Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China. jingyuanfang@sjtu.edu.cn.
¹³ NHC Key Laboratory of Digestive Diseases, Shanghai Jiao Tong University, Shanghai, China. jingyuanfang@sjtu.edu.cn.
¹⁴ State Key Laboratory for Oncogenes and Related Genes, Shanghai Jiao Tong University, Shanghai, China. jingyuanfang@sjtu.edu.cn.
¹⁵ Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. jingyuanfang@sjtu.edu.cn.
¹⁶ Division of Gastroenterology and Hepatology, Shanghai Jiao Tong University, Shanghai, China. yingxuanchen71@sjtu.edu.cn.
¹⁷ Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China. yingxuanchen71@sjtu.edu.cn.
¹⁸ NHC Key Laboratory of Digestive Diseases, Shanghai Jiao Tong University, Shanghai, China. yingxuanchen71@sjtu.edu.cn.
¹⁹ State Key Laboratory for Oncogenes and Related Genes, Shanghai Jiao Tong University, Shanghai, China. yingxuanchen71@sjtu.edu.cn.
²⁰ Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. yingxuanchen71@sjtu.edu.cn.

^# Contributed equally.

PMID: 40461825
DOI: 10.1038/s43018-025-00977-4

TRMT6-mediated tRNA m¹A modification acts as a translational checkpoint of histone synthesis and facilitates colorectal cancer progression

En-Wei Tao et al. Nat Cancer. 2025 Aug.

. 2025 Aug;6(8):1458-1476.

doi: 10.1038/s43018-025-00977-4. Epub 2025 Jun 3.

Authors

Affiliations

¹ Division of Gastroenterology and Hepatology, Shanghai Jiao Tong University, Shanghai, China.
² Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China.
³ NHC Key Laboratory of Digestive Diseases, Shanghai Jiao Tong University, Shanghai, China.
⁴ State Key Laboratory for Oncogenes and Related Genes, Shanghai Jiao Tong University, Shanghai, China.
⁵ Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁶ Division of Gastroenterology and Hepatology, Shanghai Jiao Tong University, Shanghai, China. gaoqinyan@sohu.com.
⁷ Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China. gaoqinyan@sohu.com.
⁸ NHC Key Laboratory of Digestive Diseases, Shanghai Jiao Tong University, Shanghai, China. gaoqinyan@sohu.com.
⁹ State Key Laboratory for Oncogenes and Related Genes, Shanghai Jiao Tong University, Shanghai, China. gaoqinyan@sohu.com.
¹⁰ Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. gaoqinyan@sohu.com.
¹¹ Division of Gastroenterology and Hepatology, Shanghai Jiao Tong University, Shanghai, China. jingyuanfang@sjtu.edu.cn.
¹² Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China. jingyuanfang@sjtu.edu.cn.
¹³ NHC Key Laboratory of Digestive Diseases, Shanghai Jiao Tong University, Shanghai, China. jingyuanfang@sjtu.edu.cn.
¹⁴ State Key Laboratory for Oncogenes and Related Genes, Shanghai Jiao Tong University, Shanghai, China. jingyuanfang@sjtu.edu.cn.
¹⁵ Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. jingyuanfang@sjtu.edu.cn.
¹⁶ Division of Gastroenterology and Hepatology, Shanghai Jiao Tong University, Shanghai, China. yingxuanchen71@sjtu.edu.cn.
¹⁷ Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China. yingxuanchen71@sjtu.edu.cn.
¹⁸ NHC Key Laboratory of Digestive Diseases, Shanghai Jiao Tong University, Shanghai, China. yingxuanchen71@sjtu.edu.cn.
¹⁹ State Key Laboratory for Oncogenes and Related Genes, Shanghai Jiao Tong University, Shanghai, China. yingxuanchen71@sjtu.edu.cn.
²⁰ Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. yingxuanchen71@sjtu.edu.cn.

^# Contributed equally.

PMID: 40461825
DOI: 10.1038/s43018-025-00977-4

Abstract

Transfer RNA modifications have emerged as critical regulators of translational reprogramming, yet their roles in colorectal cancer (CRC) remain largely elusive. Here, we find that tRNA N1-methyladenosine (m¹A) methyltransferase TRMT6 is upregulated in human CRC tissues and high TRMT6 expression correlates with poor survival in patients with CRC. Using orthotopic, metastatic and conditional knockout mouse models, we establish the oncogenic role of TRMT6 in CRC. Mechanistically, TRMT6 increases tRNA m¹A levels by maintaining the stability of the TRMT6-TRMT61A complex. Targeting TRMT6-mediated tRNA m¹A modification in CRC cells destabilizes tRNA-Lys-TTT-1-1 and impairs histone mRNA translation in a codon-biased manner, thereby restricting histone synthesis and hindering cell cycle progression. Our study provides evidence that TRMT6 functions as a translational checkpoint in the accelerated histone synthesis of CRC cells, highlighting TRMT6 as a promising target for potential anti-CRC therapies.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

References

1. Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71, 209–249 (2021). - PubMed
1. Dekker, E., Tanis, P. J., Vleugels, J. L. A., Kasi, P. M. & Wallace, M. B. Colorectal cancer. Lancet 394, 1467–1480 (2019). - PubMed
1. Siegel, R. L. et al. Colorectal cancer statistics, 2020. CA Cancer J. Clin. 70, 145–164 (2020). - PubMed
1. Barbieri, I. & Kouzarides, T. Role of RNA modifications in cancer. Nat. Rev. Cancer 20, 303–322 (2020). - PubMed
1. Suzuki, T. The expanding world of tRNA modifications and their disease relevance. Nat. Rev. Mol. Cell Biol. 22, 375–392 (2021). - PubMed

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82250005/National Natural Science Foundation of China (National Science Foundation of China)

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TRMT6-mediated tRNA m¹A modification acts as a translational checkpoint of histone synthesis and facilitates colorectal cancer progression

Affiliations

TRMT6-mediated tRNA m¹A modification acts as a translational checkpoint of histone synthesis and facilitates colorectal cancer progression

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding