TIP60-mediated acetylation of UHRF1 is associated with tumor cell-dependent M2-like macrophage phenotypes and aggressiveness in gastric cardia adenocarcinoma.

Abstract

Gastric cardia adenocarcinoma (GCA) is an aggressive malignancy in which immune microenvironment remodeling contributes to tumor progression. This study investigated whether Tat interactive protein, 60 kDa (TIP60)-mediated acetylation of ubiquitin-like with PHD and RING Finger domains 1 (UHRF1) regulates GCA progression and tumor cell-dependent M2-like macrophage polarization. Transcriptomic screening identified UHRF1 as a candidate oncogenic regulator, and UHRF1 was upregulated in GCA tissues and cell lines. Functional assays showed that UHRF1 promoted GCA cell proliferation, migration, invasion, cell-cycle progression, and epithelial-mesenchymal transition. Single-cell RNA sequencing and immune infiltration analyses revealed enrichment of M2 macrophages in GCA tissues and a positive association between UHRF1 expression and M2 macrophage abundance. Co-culture and conditioned-medium experiments demonstrated that tumor cell-derived UHRF1 enhanced macrophage polarization toward an M2-like phenotype, reflected by increased CD206, CD163, Arg-1, and Mrc-2 expression. Mechanistically, TIP60 interacted with UHRF1 and promoted its acetylation at K644, K646, K648, and K650. The acetylation-defective UHRF1 4KR mutant showed reduced capacity to promote GCA cell aggressiveness and tumor cell-dependent M2-like macrophage polarization. In vivo, TIP60 inhibition suppressed tumor growth, metastatic potential, and M2-like macrophage infiltration, whereas UHRF1 overexpression partially restored these effects. These findings indicate that the TIP60/UHRF1 acetylation axis promotes GCA progression by linking tumor-intrinsic epigenetic regulation with macrophage-associated immune remodeling, suggesting a potential therapeutic target for GCA.