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

Shruthy Suresh, Deniz Durakoglugil, Xiaorong Zhou, Bokai Zhu, Sarah A. Comerford, Chao Xing, Xian Jin Xie, Brian York, Kathryn A. O’Donnell

Research output: Contribution to journalArticle

4 Scopus citations

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.

Original languageEnglish (US)
Article numbere1006650
JournalPLoS genetics
Volume13
Issue number3
DOIs
StatePublished - Mar 2017

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Fingerprint Dive into the research topics of 'SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer'. Together they form a unique fingerprint.

  • Cite this