Brg1 suppress DEN-induced hepatocellular carcinogenesis in mice

Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Mutations in the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex are linked to various cancers. Brahma-related gene 1 (Brg1), a key SWI/SNF subunit, is essential for chromatin remodeling and gene regulation. However, its role in liver tumorigenesis remains unclear.

Materials and methods: To elucidate the role of Brg1 in liver carcinogenesis, we utilized a diethylnitrosamine (DEN)-induced HCC model in wild-type (Control) and hepatocyte-specific Brg1 knockout (Brg1 KO) mice. Mice were administered intraperitoneal DEN injections, and liver tumor burden was evaluated after 11 months. Molecular analyses were performed at various stages of tumor development.

Results: Brg1 expression was significantly upregulated in tumor tissues compared to adjacent non-tumor tissues in DEN-induced HCC in wild-type mice. Notably, DEN-injected Brg1 KO mice exhibited a substantial increase in liver tumor incidence, tumor multiplicity, and tumor volume compared to DEN-injected Control mice. These findings strongly indicate that Brg1 deficiency promotes liver tumorigenesis. Additionally, survival analysis revealed a significantly reduced lifespan in DEN-injected Brg1 KO mice compared to the Control group (p<0.05). Molecular analyses identified dysregulation of key oncogenic pathways in Brg1 KO mice, underscoring the role of Brg1 in maintaining liver homeostasis and tumor suppression.

Conclusion: Our data demonstrate that Brg1 acts as a tumor suppressor in hepatocytes, and its loss accelerates hepatocarcinogenesis in DEN-induced HCC models. These findings highlight the critical role of Brg1 in chromatin dynamics and liver tumor initiation, suggesting its potential as a therapeutic target in HCC.

Publication History

Article published online:
20 January 2025