IKZF3 promotes gastric cancer progression via Hedgehog signaling activation and is targetable by SANT-1

Elevated expression of Aiolos family zinc finger 3 (IKZF3), a transcription factor crucial for lymphocyte maturation, is observed in hematological cancers. However, its role in gastric cancer (GC) remains unclear. We detect the increased IKZF3 levels in GC tissues using immunohistochemical, qRT-PCR and western blot analysis. The function of IKZF3 in GC cells is further studied through CCK-8, Transwell, colony formation, scratch wound healing, and flow cytometry assays. <i>IKZF3</i> overexpression significantly promotes GC cell invasion, migration, and proliferation, whereas <i>IKZF3</i> knockdown induces cell cycle arrest at the G1/S phase. Flow cytometry confirms these alterations in cell cycle dynamics. Using the JASPAR database, we determine that IKZF3 binds to the <i>SMO</i> promoter region, thereby activating SMO expression. Notably, the SMO inhibitor SANT-1 effectively reverses IKZF3-mediated effects. Furthermore, IKZF3 promotes GC tumor growth in xenograft models. Our findings highlight the pivotal role of IKZF3 in GC progression by modulating SMO expression and activating the Hedgehog signaling pathway. Therapeutically, targeting IKZF3 with SANT-1 is promising for mitigating GC proliferation and invasion. This study provides insights into potential therapeutic approaches targeting IKZF3 for GC treatment.