{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T19:51:56Z","timestamp":1792439516640,"version":"4.5.0"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2021,3,17]],"date-time":"2021-03-17T00:00:00Z","timestamp":1615939200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,3,17]],"date-time":"2021-03-17T00:00:00Z","timestamp":1615939200000},"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":[[2021,5]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Trimethylation of Lys36 on histone 3 (H3K36me3) catalyzed by histone methyltransferase SET domain\u2010containing 2 (SETD2) is one of the most conserved epigenetic marks from yeast to mammals. SETD2 is frequently mutated in multiple cancers and acts as a tumor suppressor.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>Here, using a liver\u2010specific Setd2 depletion model, we found that <jats:italic toggle=\"yes\">Setd2<\/jats:italic> deficiency is sufficient to trigger spontaneous HCC. Meanwhile, Setd2 depletion significantly increased tumor and tumor size of a diethylnitrosamine\u2010induced HCC model. The mechanistic study showed that Setd2 suppresses HCC not only through modulating DNA damage response, but also by regulating lipid metabolism in the liver. <jats:italic toggle=\"yes\">Setd2<\/jats:italic> deficiency down\u2010regulated H3K36me3 enrichment and expression of cholesterol efflux genes and caused lipid accumulation. High\u2010fat diet enhanced lipid accumulation and promoted the development of HCC in <jats:italic toggle=\"yes\">Setd2<\/jats:italic>\u2010deficient mice. Chromatin immunoprecipitation sequencing analysis further revealed that Setd2 depletion induced c\u2010Jun\/activator protein 1 (AP\u20101) activation in the liver, which was trigged by accumulated lipid. c\u2010Jun acts as an oncogene in HCC and functions through inhibiting p53 in <jats:italic toggle=\"yes\">Setd2<\/jats:italic>\u2010deficient cells.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>We revealed the roles of <jats:italic toggle=\"yes\">Setd2<\/jats:italic> in HCC and the underlying mechanisms in regulating cholesterol homeostasis and c\u2010Jun\/AP\u20101 signaling.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.31594","type":"journal-article","created":{"date-parts":[[2020,10,15]],"date-time":"2020-10-15T14:30:26Z","timestamp":1602772226000},"page":"1797-1815","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":53,"title":["Deficiency of Histone Methyltransferase SET Domain\u2010Containing 2 in Liver Leads to Abnormal Lipid Metabolism and HCC"],"prefix":"10.1097","volume":"73","author":[{"given":"Xue\u2010Jing","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing\u2010Lan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin\u2010Gao","family":"Ju","sequence":"additional","affiliation":[{"name":"Department of Biological Repositories,Zhongnan Hospital of Wuhan 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