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

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Updated: Mar 6, 2026

An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
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An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis

Published on: September 12, 2019

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Shruthy Suresh1, Deniz Durakoglugil1, Xiaorong Zhou1,2

  • 1Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, United States of America.

Plos Genetics
|March 9, 2017
PubMed

Insights

Steroid Receptor Coactivator 2 (SRC-2) acts as a tumor suppressor in liver cancer, accelerating MYC-driven tumors when lost. Its activation of SHP, DKK4, and CADM4 inhibits liver tumorigenesis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Hepatocellular carcinoma (HCC) is a major global cancer with high mortality.
  • Previous studies identified MYC cooperation in liver tumorigenesis, revealing a tumor suppressor role for Steroid Receptor Coactivator 2 (SRC-2/Ncoa2) in liver cancer.
  • SRC-2 exhibits context-dependent roles, promoting cancer progression in prostate cancer.

Purpose of the Study:

  • To investigate if genetic loss of SRC-2 accelerates MYC-mediated liver tumorigenesis.
  • To identify direct SRC-2 target genes involved in liver tumor suppression.
  • To elucidate the mechanisms by which SRC-2 suppresses liver cancer.

Main Methods:

  • Utilized a Sleeping Beauty transposon mutagenesis screen and MYC-induced liver tumor models in mice.
  • Generated and analyzed Src-2 knockout (Src-2-/-) mice.
  • Performed RNA sequencing and in vivo chromatin immunoprecipitation assays.

Main Results:

  • Genetic loss of SRC-2 significantly increased liver tumor burden in MYC-driven models.
  • Identified direct SRC-2 target genes (SHP, DKK4, CADM4) downregulated in Src-2-/- tumors.
  • Demonstrated that SRC-2 activation of SHP, DKK4, and CADM4 suppresses liver tumorigenesis in vitro and in vivo.

Conclusions:

  • SRC-2 functions as a tumor suppressor in liver cancer, contrasting its role in other cancers.
  • SRC-2-mediated suppression of SHP, DKK4, and CADM4 is a key mechanism in preventing liver tumorigenesis.
  • SRC-2's oncogenic or tumor suppressor activity is tissue- and context-dependent.

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