SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer

Hepatocellular carcinoma (hcc) is the fifth most common solid tumor in the world and the third leading cause of cancer-associated deaths. a sleeping beauty-mediated transposon mutagenesis screen previously identified mutations that cooperate with myc to accelerate liver tumorigenesis. this revealed a tumor suppressor role for steroid receptor coactivator 2/nuclear receptor coactivator 2 (src-2/ncoa2) in liver cancer. in contrast,src-2 promotes survival and metastasis in prostate cancer cells,suggesting a tissue-specific and context-dependent role for src-2 in tumorigenesis. to determine if genetic loss of src-2 is sufficient to accelerate myc-mediated liver tumorigenesis,we bred src-2-/-mice with a myc-induced liver tumor model and observed a significant increase in liver tumor burden. rna sequencing of liver tumors and in vivo chromatin immunoprecipitation assays revealed a set of direct target genes that are bound by src-2 and exhibit downregulated expression in src-2-/-liver tumors. we demonstrate that activation of shp (small heterodimer partner),dkk4 (dickkopf-4),and cadm4 (cell adhesion molecule 4) by src-2 suppresses tumorigenesis in vitro and in vivo. these studies suggest that src-2 may exhibit oncogenic or tumor suppressor activity depending on the target genes and nuclear receptors that are expressed in distinct tissues and illuminate the mechanisms of tumor suppression by src-2 in liver. © 2017 suresh et al.