Epigenetic upregulation of PAPSS2 drives proliferation, migration, angiogenesis, and M2 macrophage infiltration in gastric cancer

Abstract Objective 3’-Phosphoadenosine 5’-phosphosulfate (PAPS) synthase 2 (PAPSS2) catalyzes the rate-limiting step in sulfation metabolism by generating the universal sulfate donor PAPS. However, its biological and clinical significance in gastric cancer (GC) remains poorly understood. Methods We analyzed PAPSS2 expression, prognostic value, immune infiltration correlates, promoter methylation, and histone acetylation patterns using public databases. Expression levels were validated by qRT-PCR and western blotting. Functional assays —CCK-8, Transwell migration/invasion, and HUVEC tube formation assays— assessed the oncogenic roles of PAPSS2. Finally, we performed ChIP assay to investigate the epigenetic mechanism driving PAPSS2 upregulation in GC. Results PAPSS2 was significantly upregulated in GC tissues and cell lines, and high PAPSS2 expression correlated with poorer patient survival. Co-expression network analysis linked PAPSS2-associated genes to extracellular matrix organization, angiogenesis, and metastatic progression. Functional knockdown of PAPSS2 suppressed GC cell proliferation, migration, and invasion; impaired VEGFA-driven angiogenesis; and inhibited M2 macrophage polarization. Mechanistically, promoter hypomethylation and p300/CBP-mediated H3K27 acetylation may contribute to PAPSS2 overexpression in GC cells. Conclusion Epigenetically driven PAPSS2 overexpression promotes GC cell proliferation and migration, potentiates VEGFA-dependent angiogenesis, and facilitates M2 macrophage polarization, highlighting PAPSS2 as a potential therapeutic target in GC.