Researchers Reveal New Mechanism by Which tRNA Modifications Promote Colorectal Cancer

Colorectal cancer (CRC) is the third most common cancer worldwide (nearly 2 million, second only to lung cancer and breast cancer), and the second most common cancer in terms of deaths (nearly 1 million, second only to lung cancer). Colorectal cancer is usually asymptomatic in the early stages and is often diagnosed in the late stages. Therefore, active treatments such as surgery, radiotherapy, and chemotherapy are required. However, these treatments also have limitations. Surgery has a high recurrence rate, radiotherapy can cause serious complications, and chemotherapy often leads to drug resistance, with about 50% of patients experiencing recurrence. In addition, the incidence of colorectal cancer has been increasing in young people under the age of 50 over the past 30 years. This makes colorectal cancer a major public health and socioeconomic issue.

In recent years, transfer RNA (tRNA) modification, as an important component of epigenetic transcriptional regulation, has received widespread attention in the field of tumor research. tRNA is not only a "porter" in the translation process, but its own chemical modification can significantly affect translation efficiency, codon recognition preference, and mRNA selective expression. tRNA modifications have emerged as key regulators of translational reprogramming, but their roles in colorectal cancer (CRC) remain largely unknown.

Recently, researchers from Shanghai Jiao Tong University School of Medicine in China published a research paper titled "TRMT6-mediated tRNA m1A modification acts as a translational checkpoint of histone synthesis and facilitates colorectal cancer progression" in Nature Cancer, a subsidiary of Nature. The study found that TRMT6-mediated tRNA N1-methyladenosine (m1A) modification, as a translational checkpoint of histone synthesis, promotes the occurrence and development of colorectal cancer. This discovery provides a new perspective for a deeper understanding of the molecular mechanism of colorectal cancer progression.

T6 is upregulated in human colorectal cancer (CRC) tissues, and high expression of TRMT6 is associated with poor prognosis in colorectal cancer patients. The research team used in situ, metastatic and conditional gene knockout mouse models to further establish the carcinogenic role of TRMT6 in colorectal cancer.

Mechanistic studies revealed that TRMT6 stabilizes the TRMT6/TRMT61A complex and enhances the tRNA m1A modification level, thereby maintaining the stability of specific tRNAs (especially tRNA-Lys-TTT-1-1). TRMT6 deficiency leads to rapid degradation of the tRNA, selectively reduces the translation efficiency of histone mRNAs rich in AAA and AAG codons, thereby reducing histone synthesis in colorectal cancer cells and blocking their cell cycle progression. However, it does not affect the function of normal intestinal epithelial cells. This suggests that targeting TRMT6 has good tumor specificity and therapeutic window.

Figure 1. A schematic model illustrating the role and underlying mechanism of TRMT6-mediated tRNA m1A modification in the regulating CRC progression. (Tao, En-Wei, et al. 2025)

In addition, the research team also proposed an innovative treatment strategy: using cholesterol-conjugation modified siRNA to specifically target TRMT6. Animal experimental results showed that this strategy can effectively inhibit CRC tumor growth and liver metastasis. Combined with the CDK4/6 inhibitor Palbociclib, it further enhances the anti-tumor effect, providing a new idea for the precision treatment of CRC.

In summary, this study not only reveals the key regulatory mechanisms in the occurrence and development of CRC, but also lays a solid theoretical foundation and preliminary evidence for the clinical development of innovative anti-tumor therapies based on tRNA modification.