Deficiency of Histone Methyltransferase SET Domain‐Containing 2 in Liver Leads to Abnormal Lipid Metabolism and HCC

Background and Aims Trimethylation of Lys36 on histone 3 (H3K36me3) catalyzed by histone methyltransferase SET domain‐containing 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. Approach and Results Here, using a liver‐specific Setd2 depletion model, we found that Setd2 deficiency is sufficient to trigger spontaneous HCC. Meanwhile, Setd2 depletion significantly increased tumor and tumor size of a diethylnitrosamine‐induced 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. Setd2 deficiency down‐regulated H3K36me3 enrichment and expression of cholesterol efflux genes and caused lipid accumulation. High‐fat diet enhanced lipid accumulation and promoted the development of HCC in Setd2 ‐deficient mice. Chromatin immunoprecipitation sequencing analysis further revealed that Setd2 depletion induced c‐Jun/activator protein 1 (AP‐1) activation in the liver, which was trigged by accumulated lipid. c‐Jun acts as an oncogene in HCC and functions through inhibiting p53 in Setd2 ‐deficient cells. Conclusions We revealed the roles of Setd2 in HCC and the underlying mechanisms in regulating cholesterol homeostasis and c‐Jun/AP‐1 signaling.