{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:46:20Z","timestamp":1787013980336,"version":"build-2736575974"},"reference-count":45,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2023,9,12]],"date-time":"2023-09-12T00:00:00Z","timestamp":1694476800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100019018","name":"Chinese Academy of Medical Sciences Initiative for Innovative Medicine","doi-asserted-by":"publisher","award":["2021\u2010I2M\u20101\u2010022"],"award-info":[{"award-number":["2021\u2010I2M\u20101\u2010022"]}],"id":[{"id":"10.13039\/501100019018","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>N6\u2010methyladenosine (m6A) is the most abundant internal modification in eukaryotic RNA and involved in the carcinogenesis of various malignancies. However, the functions and mechanisms of m6A in gallbladder cancer (GBC) remain unclear. In this study, we investigated the role and underlying mechanism of the RNA\u2010binding protein YT521\u2010B homology domain\u2010containing family protein 2 (YTHDF2), an m6A reader, in GBC. Herein, we detected that YTHDF2 was remarkably upregulated in GBC tissues compared to normal gallbladder tissues. Functionally, YTHDF2 overexpression promoted the proliferation, tumor growth, migration, and invasion of GBC cells while inhibiting the apoptosis in vitro and in vivo. Conversely, YTHDF2 knockdown induced opposite results. Mechanistically, we further investigated the underlying mechanism by integrating RNA immunoprecipitation sequencing (RIP\u2010seq), m6A\u2010modified RIP\u2010seq, and RNA sequencing, which revealed that death\u2010associated protein kinase 3 (DAPK3) is a direct target of YTHDF2. YTHDF2 binds to the 3\u2032\u2010UTR of DAPK3 mRNA and facilitates its degradation in an m6A\u2010dependent manner. DAPK3 inhibition restores the tumor\u2010suppressive phenotype induced by YTHDF2 deficiency. Moreover, the YTHDF2\/DAPK3 axis induces the resistance of GBC cells to gemcitabine. In conclusion, we reveal the oncogenic role of YTHDF2 in GBC, demonstrating that YTHDF2 increases the mRNA degradation of the tumor suppressor DAPK3 in an m6A\u2010dependent way, which promotes GBC progression and desensitizes GBC cells to gemcitabine. Our findings provide novel insights into potential therapeutic strategies for GBC.<\/jats:p>","DOI":"10.1111\/cas.15953","type":"journal-article","created":{"date-parts":[[2023,9,13]],"date-time":"2023-09-13T00:09:46Z","timestamp":1694563786000},"page":"4299-4313","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["<scp>YTHDF2<\/scp>\n                    promotes gallbladder cancer progression and gemcitabine resistance via\n                    <scp>m6A<\/scp>\n                    \u2010dependent\n                    <scp>DAPK3<\/scp>\n                    degradation"],"prefix":"10.1111","volume":"114","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8497-8468","authenticated-orcid":false,"given":"Xuesong","family":"Bai","sequence":"first","affiliation":[{"name":"Department of General Surgery State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College 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