HNF4A-BAP31-VDAC1 axis synchronously regulates cell proliferation and ferroptosis in gastric cancer

B cell receptor associated protein 31 (BAP31) is closely associated with tumor progression, while the role and mechanism of BAP31 in gastric cancer (GC) remains unknown. This study explored that BAP31 was upregulated in GC tissues and high expression indicated poor survival of GC patients. BAP31 knockdown inhibited cell growth and induced G1/S arrest. Moreover, BAP31 attenuation increased the lipid peroxidation level of the membrane and facilitated cellular ferroptosis. Mechanistically, BAP31 regulated cell proliferation and ferroptosis by directly binding to VDAC1 and affected VDAC1 oligomerization and polyubiquitination. HNF4A was bound to BAP31 at the promoter and increased its transcription. Furthermore, knockdown of BAP31 inclined to make GC cells vulnerable to 5-FU and ferroptosis inducer, erastin, in vivo and in vitro. Our work suggests that BAP31 may serve as prognostic factor for gastric cancer and act as potential therapeutic strategy for gastric cancer.

Automated summary

BAP31 is upregulated in gastric cancer tissues and high expression is associated with poor survival of patients. BAP31 knockdown inhibits cell growth, induces G1/S arrest, and promotes cellular ferroptosis by increasing membrane lipid peroxidation. BAP31 directly binds to VDAC1, affecting its oligomerization and polyubiquitination, and is regulated by HNF4A at the promoter. Knockdown of BAP31 sensitizes gastric cancer cells to 5-FU and the ferroptosis inducer erastin.