Testin and filamin-C downregulation by acetylated Siah2 increases invasiveness of Helicobacter pylori-infected gastric cancer cells

Siah2 acetylation promotes gastric cancer invasiveness. H. pylori enhances Siah2 acetylation by p300 at the K139 residue. Acetylation at K139 enhances Siah2 stability, prevents its proteasomal degradation and therefore, Siah2 targets TES and FLN-C are more effectively degraded in the H. pylori-infected gastric epithelium. TES and FLN-C downregulation impairs actin filament organization, filopodia formation and promotes invasiveness of gastric epithelial cancer cells. [Display omitted] •ac-K139Siah2 enhances TES and FLN-C degradation.•Low level of TES and FLN-C promotes gastric cancer invasiveness.•ac-K139Siah2 induce lamellipodia formation.•K139R mutation of Siah2 reverses the effect of Siah2 on TES and FLN-C. Helicobacter pylori is the strongest known risk-factor for gastric cancer. However, its role in gastric cancer metastasis remains unclear. Previously we have reported that H. pylori promotes gastric cancer invasiveness by stabilizing the E3 ubiquitin ligase Siah2 which is mediated by Siah2 acetylation at Lys 139 (K139) residue. Here we identify that cell adhesion-related proteins testin (TES) and filamin-C (FLN-C) interact with Siah2 and get proteasomally degraded. The efficiency of TES and FLN-C degradation is significantly potentiated by K139-acetylated Siah2 (ac-K139 Siah2) in infected gastric cancer cells (GCCs). ac-Siah2-mediated downregulation of TES and FLN-C disrupts filopodia structures but promotes lamellipodia formation and enhances invasiveness and migration of infected GCCs. Since H. felis-infected mice as well as human gastric cancer biopsy samples also show high level of ac-K139 Siah2 and downregulated TES and FLN-C, we believe that acetylation of Siah2 is an important checkpoint that can be useful for therapeutic intervention.