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

PLoS Genet. 2017 Mar 8;13(3):e1006650. doi: 10.1371/journal.pgen.1006650. eCollection 2017 Mar.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Antineoplastic Agents / chemistry
  • Carcinogenesis
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism*
  • Cell Adhesion Molecules / metabolism
  • Cell Proliferation
  • Cell Survival
  • Chromatin Immunoprecipitation
  • DNA Transposable Elements
  • Female
  • Gene Deletion
  • Hep G2 Cells
  • Humans
  • Immunoglobulins / metabolism
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Nude
  • Mutagenesis
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Nuclear Receptor Coactivator 2 / genetics
  • Nuclear Receptor Coactivator 2 / metabolism*
  • Prostatic Neoplasms / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Sequence Analysis, RNA

Substances

  • Antineoplastic Agents
  • CADM4 protein, human
  • Cell Adhesion Molecules
  • DKK4 protein, human
  • DNA Transposable Elements
  • Immunoglobulins
  • Intercellular Signaling Peptides and Proteins
  • NCOA2 protein, human
  • Nuclear Receptor Coactivator 2
  • Proto-Oncogene Proteins c-myc
  • Receptors, Cytoplasmic and Nuclear
  • nuclear receptor subfamily 0, group B, member 2