GATA4 loss of function in liver cancer impedes precursor to hepatocyte transition

J Clin Invest. 2017 Sep 1;127(9):3527-3542. doi: 10.1172/JCI93488. Epub 2017 Jul 31.


The most frequent chromosomal structural loss in hepatocellular carcinoma (HCC) is of the short arm of chromosome 8 (8p). Genes on the remaining homologous chromosome, however, are not recurrently mutated, and the identity of key 8p tumor-suppressor genes (TSG) is unknown. In this work, analysis of minimal commonly deleted 8p segments to identify candidate TSG implicated GATA4, a master transcription factor driver of hepatocyte epithelial lineage fate. In a murine model, liver-conditional deletion of 1 Gata4 allele to model the haploinsufficiency seen in HCC produced enlarged livers with a gene expression profile of persistent precursor proliferation and failed hepatocyte epithelial differentiation. HCC mimicked this gene expression profile, even in cases that were morphologically classified as well differentiated. HCC with intact chromosome 8p also featured GATA4 loss of function via GATA4 germline mutations that abrogated GATA4 interactions with a coactivator, MED12, or by inactivating mutations directly in GATA4 coactivators, including ARID1A. GATA4 reintroduction into GATA4-haploinsufficient HCC cells or ARID1A reintroduction into ARID1A-mutant/GATA4-intact HCC cells activated hundreds of hepatocyte genes and quenched the proliferative precursor program. Thus, disruption of GATA4-mediated transactivation in HCC suppresses hepatocyte epithelial differentiation to sustain replicative precursor phenotype.

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism*
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Lineage
  • Cell Proliferation
  • Epithelial Cells / cytology
  • Female
  • GATA4 Transcription Factor / genetics
  • GATA4 Transcription Factor / metabolism*
  • Gene Deletion
  • Germ-Line Mutation
  • Haploinsufficiency
  • Hep G2 Cells
  • Hepatocytes / cytology
  • Hepatocytes / metabolism*
  • Humans
  • Inflammation
  • Karyotyping
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Mutation
  • Phenotype
  • Polymorphism, Single Nucleotide


  • GATA4 Transcription Factor
  • GATA4 protein, human
  • Gata4 protein, mouse