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

• Published in: PLoS genetics Vol. 13; no. 3; p. e1006650
• Main Authors: Suresh, Shruthy, Durakoglugil, Deniz, Zhou, Xiaorong, Zhu, Bokai, Comerford, Sarah A, Xing, Chao, Xie, Xian-Jin, York, Brian, O'Donnell, Kathryn A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08.03.2017; Public Library of Science (PLoS)
• Subjects: Alleles; Animals; Antineoplastic Agents - chemistry; Biology and Life Sciences; Cancer; Carcinogenesis; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Cell adhesion; Cell Adhesion Molecules - metabolism; Cell Proliferation; Cell Survival; Cellular biology; Chromatin Immunoprecipitation; Chromosomes; Computer and Information Sciences; DNA Transposable Elements; Female; Gene Deletion; Gene expression; Gene mutation; Genes; Genetic aspects; Genomics; Hep G2 Cells; Hepatocellular carcinoma; Humans; Immunoglobulins - metabolism; Intercellular Signaling Peptides and Proteins - metabolism; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Male; Medical research; Medicine; Medicine and Health Sciences; Metastasis; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; Molecular biology; Mutagenesis; Mutation; Neoplasm Metastasis; Neoplasm Transplantation; Nuclear Receptor Coactivator 2 - genetics; Nuclear Receptor Coactivator 2 - metabolism; Oncogenes; Prostate; Prostate cancer; Prostatic Neoplasms - metabolism; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Receptors, Cytoplasmic and Nuclear - metabolism; Research and Analysis Methods; Rodents; Sequence Analysis, RNA; Signal transduction; Studies; Thyroid gland; Tumor suppressor genes; Tumorigenesis; Tumors
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1006650

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.