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However, the role of A-to-I tRNA modification in colorectal cancer (CRC) remains poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      tRNA modification was profiled by LC-MS in paired CRC and adjacent normal tissues (\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u200970). The clinical significance of adenosine deaminase tRNA specific 2 (ADAT2) was evaluated using in-house (\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u2009157) and TCGA cohorts (\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u2009283). 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Among 32 tRNA nucleotide modifications, A-to-I modification is the top enriched tRNA modification in CRC tumors compared to paired adjacent normal tissues (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.001). 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\/\u03b2-catenin signaling. We revealed HDAC7 as a downstream target, whereby ADAT2 promotes HDAC7 translation in an A-to-I dependent fashion. HDAC7 interacts with \u03b2-catenin, leading to its activation and nuclear translocation. For translational value, ADAT2 promotes chemoresistance in CRC, and targeting ADAT2 by VNP-encapsulated ADAT2-siRNA promoted Oxaliplatin and 5-Fluorouracil efficacy to suppress CRC growth.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>ADAT2-driven tRNA A-to-I modification promotes CRC tumorigenesis and chemoresistance via HDAC7-WNT\/\u03b2-catenin axis, and is an independent prognostic factor.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12943-026-02618-5","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T10:24:40Z","timestamp":1773743080000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["ADAT2-mediated A-to-I tRNA modification promotes oncogenic translation and colorectal cancer progression and chemoresistance"],"prefix":"10.1186","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0975-6926","authenticated-orcid":false,"given":"Cillian H.","family":"Cheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fenfen","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianming","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Jiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danyu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liufang","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruizhi","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinyao","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1362-3541","authenticated-orcid":false,"given":"Chi Chun","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,17]]},"reference":[{"key":"2618_CR1","first-page":"10","volume":"75","author":"RL Siegel","year":"2025","unstructured":"Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. 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All the animal studies were performed in accordance with guidelines and approved by the Animal Experimentation Ethics Committee of the Chinese University of Hong Kong (Ref number: No. 23-138-MIS and 24-304-GRF).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"118"}}