Transglutaminase 2 exacerbates ovarian cancer survival by directly inactivating GSK3β

Abstract

Elevated expression of transglutaminase 2 (TGase 2, EC 2.3.2.13, protein-glutamine gamma-glutamyltransferase, gene name TGM2) is known 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, presenting a significant clinical challenge. Drug-resistant ovarian cancer cells exhibit markedly higher levels of TGase 2 compared to normal ovarian epithelium, which is associated with EMT activation, enabling them to evade chemotherapy effects. Intracellular TGase 2 is recognized as a key factor in maintaining the mesenchymal phenotype. Therefore, while EMT expression can be effectively reversed by inhibiting TGase 2, the underlying mechanism of this effect remains unclear. We found that TGase 2 promotes EMT by directly binding to glycogen synthase kinase-3 beta (GSK3 beta), promoting the stabilization of beta-catenin. Domain mapping revealed that the N-terminus of TGase 2 interacts with the mid-region of GSK3 beta, leading to the autophagic degradation of GSK3 beta. Pharmacological disruption of this N-terminal interaction by streptonigrin, in combination with standard chemotherapy, extended overall survival in a xenograft model of ovarian cancer. This study identified TGase 2 as a pivotal regulator of EMT-driven metastasis and drug resistance.