GAL3ST1-Mediated Histone Tyrosine Sulfation Induced by Cancer-Associated Fibroblasts Promotes Gastric Cancer Metastasis

Gastric cancer metastasis involves the interaction between tumor cells and their stromal microenvironment. Cancer-associated fibroblasts (CAF) play a pivotal role in this process, and elucidation of the molecular mechanisms underlying gastric cancer cell-CAF interactions could uncover potential therapeutic targets to block metastatic progression. In this study, through transcriptomic profiling of gastric cancer cell-CAF communications, we identified galactose-3-O-sulfotransferase 1 (GAL3ST1) as a key regulator of CAF-induced gastric cancer cell metastatic potential. Mechanistically, GAL3ST1 functioned as a histone sulfotransferase to sulfate nascent histone H3 at tyrosine 99 (H3Y99sulf) in the cytosol of gastric cancer cells. The sulfated histones were subsequently translocated to the nucleus via AP2B1, in which they recruited KAT2A to establish H3K56 acetylation marks that resulted in activation of β-catenin transcription and drove epithelial-mesenchymal transition. Furthermore, CAF-derived SEMA7A engaged ITGB1 on gastric cancer cells and initiated ERK1/2-CEBPB signaling to transcriptionally upregulate GAL3ST1. Collectively, these findings reveal a role for GAL3ST1 in histone sulfation-mediated epigenetic regulation and elucidate the SEMA7A/GAL3ST1/H3Y99sulf axis as a crucial mediator of tumor-stromal cross-talk in gastric cancer metastasis. Significance: Cancer-associated fibroblasts stimulate GAL3ST1 expression in gastric cancer cells that catalyzes histone H3 sulfation to enable β-catenin-driven metastasis, highlighting the potential of disrupting stromal-mediated epigenetic reprogramming to improve patient outcomes.