Abstract Elevated expression of transglutaminase 2 (TGase 2, EC 2.3.2.13, protein-glutamine g-glutamyltransferase, gene name TGM2) is recognized as one of the most upregulated genes during epithelial-mesenchymal transition (EMT) in ovarian cancer. Despite initial complete responses to conventional chemotherapy, ovarian cancer often recurs with metastasis, posing a major clinical challenge. Drug-resistant ovarian cancer cells show significantly higher levels of TGase 2 compared to normal ovarian epithelium, which is associated with EMT activation that enables them to evade chemotherapy effects. Intracellular TGase 2 is identified as a key factor in maintaining the mesenchymal phenotype. Therefore, while EMT can be effectively reversed by inhibiting TGase 2, the precise mechanism behind this effect remains unclear. We found that TGase 2 promotes EMT by directly binding to glycogen synthase kinase-3β (GSK3β), aiding in the stabilization of β-catenin. Domain mapping revealed that the N-terminus of TGase 2 interacts with the mid-region of GSK3β, leading to the autophagic degradation of GSK3β. Pharmacological disruption of this N-terminal interaction using streptonigrin, combined with standard chemotherapy, extended survival in a xenograft model of ovarian cancer. This study highlights TGase 2 as a key regulator of EMT-driven metastasis and drug resistance.
Kim et al. (Wed,) studied this question.
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