ADAT2-mediated A-to-I tRNA modification promotes oncogenic translation and colorectal cancer progression and chemoresistance

作者：Hao Cheng, Fenfen Ji, Jianming Shen, Ying Jiao, D.M. Chen, Huan Yang, Litao Ye, Ruizhi Tao, Qinyao Wei, Wei Kang, Jun Yu, Chi Chun Wong · 发表于：Molecular Cancer · 年份：2026 · DOI：10.1186/s12943-026-02618-5 · 被引用次数：1 · 研究领域：RNA modifications and cancer、RNA regulation and disease、RNA and protein synthesis mechanisms

BACKGROUND: Adenosine-to-Inosine (A-to-I) modification is one of the most common transfer RNA (tRNA) modifications in humans. However, the role of A-to-I tRNA modification in colorectal cancer (CRC) remains poorly understood. METHODS: tRNA modification was profiled by LC-MS in paired CRC and adjacent normal tissues (N = 70). The clinical significance of adenosine deaminase tRNA specific 2 (ADAT2) was evaluated using in-house (N = 157) and TCGA cohorts (N = 283). The function of ADAT2 in CRC was determined in intestine-specific ADAT2 knockout mice. Mechanism of ADAT2 was assessed by integrated RNA-sequencing, tRNA-sequencing, and ribosome-sequencing analyses. RESULTS: Among 32 tRNA nucleotide modifications, A-to-I modification is the top enriched tRNA modification in CRC tumors compared to paired adjacent normal tissues (P < 0.001). Consistently, A-to-I modification enzyme ADAT2 is elevated in CRC and associated with poor patient survival in independent patient cohorts. Functionally, ADAT2 overexpression promotes malignant phenotypes in CRC cells and patient-derived CRC organoids, whereas ADAT2 knockout exerts opposite effects. Intestine-specific ADAT2 knockout mice showed attenuated colorectal tumorigenesis. Integrated sequencing identified that ADAT2 boosts translation efficiency of genes highly dependent on A-to-I codons, specifically enriched in WNT/β-catenin signaling. We revealed HDAC7 as a downstream target, whereby ADAT2 promotes HDAC7 translation in an A-to-I dependen...