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

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 (K) 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 K-acetylated Siah2 (ac-K 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-K Siah2 and downregulated TES and FLN-C, we believe that acetylation of Siah2 is an important checkpoint that can be useful for therapeutic intervention.