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. Sun el al. uncover context-specific roles for the SWI/SNF component Arid1a in liver cancer, where elevated Arid1a promotes tumor initiation through CYP450-mediated oxidative stress, whereas reduced Arid1a in established tumors increases metastasis due to reduced expression of inhibitory factors.
- SWI/SNF chromatin-remodeling complex
- hepatocellular carcinoma
- mouse models
ASJC Scopus subject areas
- Cancer Research