{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T14:21:06Z","timestamp":1780582866839,"version":"3.54.1"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2021,6,18]],"date-time":"2021-06-18T00:00:00Z","timestamp":1623974400000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Cholangiocarcinoma (CCA) is a devastating disease often detected at advanced stages when surgery cannot be performed. Conventional and targeted systemic therapies perform poorly, and therefore effective drugs are urgently needed. Different epigenetic modifications occur in CCA and contribute to malignancy. Targeting epigenetic mechanisms may thus open therapeutic opportunities. However, modifications such as DNA and histone methylation often coexist and cooperate in carcinogenesis. We tested the therapeutic efficacy and mechanism of action of a class of dual G9a histone\u2010methyltransferase and DNA\u2010methyltransferase 1 (DNMT1) inhibitors.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>Expression of <jats:italic toggle=\"yes\">G9a<\/jats:italic>, <jats:italic toggle=\"yes\">DNMT1<\/jats:italic>, and their molecular adaptor, ubiquitin\u2010like with PHD and RING finger domains\u20101 (<jats:italic toggle=\"yes\">UHRF1<\/jats:italic>), was determined in human CCA. We evaluated the effect of individual and combined pharmacological inhibition of G9a and DNMT1 on CCA cell growth. Our lead G9a\/DNMT1 inhibitor, CM272, was tested in human CCA cells, patient\u2010derived tumoroids and xenograft, and a mouse model of cholangiocarcinogenesis with hepatocellular deletion of c\u2010Jun\u2010N\u2010terminal\u2010kinase (Jnk)\u20101\/2 and diethyl\u2010nitrosamine (DEN) plus CCl<jats:sub>4<\/jats:sub> treatment (Jnk<jats:sup>\u0394hepa<\/jats:sup> + DEN + CCl<jats:sub>4<\/jats:sub> mice). We found an increased and correlative expression of <jats:italic toggle=\"yes\">G9a<\/jats:italic>, <jats:italic toggle=\"yes\">DNMT1<\/jats:italic>, and <jats:italic toggle=\"yes\">UHRF1<\/jats:italic> in CCAs. Cotreatment with independent pharmacological inhibitors G9a and DNMT1 synergistically inhibited CCA cell growth. CM272 markedly reduced CCA cell proliferation and synergized with Cisplatin and the ERBB\u2010targeted inhibitor, Lapatinib. CM272 inhibited CCA tumoroids and xenograft growth and significantly antagonized CCA progression in Jnk<jats:sup>\u0394hepa<\/jats:sup> + DEN + CCl<jats:sub>4<\/jats:sub> mice without apparent toxicity. Mechanistically, CM272 reprogrammed the tumoral metabolic transcriptome and phenotype toward a differentiated and quiescent status.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Dual targeting of G9a and DNMT1 with epigenetic small molecule inhibitors such as CM272 is a potential strategy to treat CCA and\/or enhance the efficacy of other systemic therapies.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.31642","type":"journal-article","created":{"date-parts":[[2020,11,22]],"date-time":"2020-11-22T03:52:37Z","timestamp":1606017157000},"page":"2380-2396","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":51,"title":["Dual Targeting of G9a and DNA Methyltransferase\u20101 for the Treatment of Experimental Cholangiocarcinoma"],"prefix":"10.1097","volume":"73","author":[{"given":"Leticia","family":"Colyn","sequence":"first","affiliation":[{"name":"Hepatology Program,CIMA,University of Navarra,Pamplona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"B\u00e1rcena\u2010Varela","sequence":"additional","affiliation":[{"name":"Hepatology Program,CIMA,University of Navarra,Pamplona,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"\u00c1lvarez\u2010Sola","sequence":"additional","affiliation":[{"name":"Hepatology Program,CIMA,University of Navarra,Pamplona,Spain"},{"name":"CIBERehd,Instituto de Salud Carlos III,Madrid,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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