Combined Inhibition of EZH2 and HMGA1 Affects Gastric Carcinoma Cell Viability
: Background: With limited treatment options and suboptimal clinical outcomes, gastric adenocarcinoma (GAC) remains a major global health burden. Enhancer of zeste homolog 2 (EZH2) and high mobility group A1 (HMGA1) are frequently upregulated in several human cancers and are associated with key oncogenic processes, including tumor growth, metastasis, and chemoresistance. This study aimed to evaluate the expression and relationship of EZH2 and HMGA1 in gastric cancer and to investigate the potential therapeutic effects of their individual or combined pharmacological inhibition. Methods: TCGA datasets, tissue microarray immunohistochemistry, and gastric cancer cell lines were used to assess HMGA1 and EZH2 expression. Following treatment with GSK126 (Enhancer of zeste homolog 2 inhibitor), an EZH2 (Enhancer of zeste homolog 2) inhibitor, and Trabectedin (ET-743), an HMGA1-targeting compound, administered alone or in combination, functional assays were performed to evaluate cell viability and apoptosis. The Loewe synergy model was applied to determine drug–drug interactions, and additional experiments investigated whether 5-fluorouracil (5-FU) treatment enhanced chemosensitivity. Results: HMGA1 and EZH2 were markedly overexpressed and positively correlated in gastric cancer tissues and cell lines. Both ET-743 and GSK126 significantly reduced gastric cancer cell viability, and their combination produced a stronger cytotoxic effect, consistent with Loewe model predictions. Both drugs induced apoptosis, with combination treatment further enhancing this effect. Additionally, ET-743 or GSK126 substantially increased the cytotoxic response to 5-FU, suggesting enhanced susceptibility to fluoropyrimidine-based chemotherapy. Conclusions: HMGA1 and EZH2 cooperate in driving gastric cancer progression, and their pharmacological inhibition exerts potent, complementary antitumor effects while sparing normal gastric cells. These findings support the potential clinical application of ET-743 and GSK126 as standalone agents or in combination with standard chemotherapy for gastric cancer treatment.