Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer

Cancer Cell. 2017 Nov 13;32(5):574-589.e6. doi: 10.1016/j.ccell.2017.10.007.

Abstract

ARID1A, an SWI/SNF chromatin-remodeling gene, is commonly mutated in cancer and hypothesized to be tumor suppressive. In some hepatocellular carcinoma patients, ARID1A was highly expressed in primary tumors but not in metastatic lesions, suggesting that ARID1A can be lost after initiation. Mice with liver-specific homozygous or heterozygous Arid1a loss were resistant to tumor initiation while ARID1A overexpression accelerated initiation. In contrast, homozygous or heterozygous Arid1a loss in established tumors accelerated progression and metastasis. Mechanistically, gain of Arid1a function promoted initiation by increasing CYP450-mediated oxidative stress, while loss of Arid1a within tumors decreased chromatin accessibility and reduced transcription of genes associated with migration, invasion, and metastasis. In summary, ARID1A has context-dependent tumor-suppressive and oncogenic roles in cancer.

Keywords: ARID1A; SWI/SNF chromatin-remodeling complex; epigenetics; hepatocellular carcinoma; metastasis; mouse models.

MeSH terms

  • Animals
  • Blotting, Western
  • Carcinogenesis / genetics
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor
  • Humans
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Neoplasm Metastasis
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Oncogenes / genetics*
  • RNA Interference
  • Transcription Factors

Substances

  • Arid1a protein, mouse
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Transcription Factors