GATA2-driven ZNF486-JAM2 activation collaboratively counteracts epithelial-mesenchymal transition and in vitro invasion in endometrial cancer

Abstract

Objective To investigate the role and molecular mechanism of the GATA2/ZNF486/JAM2 transcriptional regulatory axis in the invasion and migration of Uterine Corpus Endometrial Carcinoma (UCEC). Methods We employed reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB) to assess the expression levels of ZNF486, GATA2, and JAM2 in UCEC cell lines. Lentivirus-mediated overexpression and knockdown cell lines were established, and CCK-8, colony formation, Transwell, and wound healing assays were performed to evaluate cell proliferation, invasion, and migration. WB and immunofluorescence were used to detect changes in epithelial-mesenchymal transition (EMT) markers. The direct binding and transcriptional activation of target gene promoters by transcription factors were confirmed through ChIP-qPCR and dual-luciferase reporter assays. Results ZNF486 was significantly downregulated in UCEC. Its overexpression upregulated E-cadherin, downregulated N-cadherin and Vimentin, and markedly inhibited cell proliferation, invasion, and migration. Mechanistically, ZNF486 directly bound to and transcriptionally activated the JAM2 promoter; knockdown of JAM2 partially attenuated the tumor-suppressive effects of ZNF486. Furthermore, GATA2 was identified as an upstream transcription factor that directly activated ZNF486 transcription; knockdown of ZNF486 abrogated the tumor-suppressive effects induced by GATA2 overexpression. Conclusion GATA2 inhibits EMT, invasion, and migration in UCEC by transcriptionally activating the ZNF486-JAM2 axis. This pathway provides a potential molecular framework for understanding UCEC progression.