PARK2-Mediated PGK1 Degradation Suppresses Partial Epithelial-Mesenchymal Transition and Metastasis in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targeted therapies. Phosphoglycerate kinase 1 (PGK1) drives TNBC progression, but mechanisms governing its protein stability remain unclear. This study aims to identify the E3 ubiquitin ligase responsible for PGK1 degradation and evaluate its therapeutic potential against metastasis.

Clinical datasets and 50 human TNBC tissues were analyzed via multiplex immunohistochemistry. Co-immunoprecipitation, ubiquitination linkage assays, and structural modeling were utilized for in vitro mechanistic studies in TNBC cells. Additionally, functional impacts on epithelial-mesenchymal transition (EMT) and metastasis were evaluated using transwell assays and an in vivo mouse lung metastasis model.

Parkinson disease protein 2 (PARK2) is a novel E3 ubiquitin ligase that mediates proteasomal degradation of PGK1 in TNBC cells. Elevated PGK1 expression and reduced PARK2 expression in TNBC, with high PGK1 levels correlating with unfavorable overall survival (HR: 2.138, 95%CI:1.001 to 4.569, p = 0.049). PARK2 physically binds PGK1 via its RING2 domain and promotes K48-linked polyubiquitination, leading to proteasomal degradation. A significant negative correlation between PARK2 and PGK1 at the protein levels were confirmed in 50 TNBC tumor tissues (Spearman’s rho = −0.58, p < 0.001). Functionally, PARK2 overexpression reduced mesenchymal markers (Vimentin, Snail1, Slug) and suppressed migration and invasion of TNBC cells, effects that were reversed by PGK1 overexpression. PARK2 significantly inhibited PGK1-mediated lung metastasis in in vivo tail vein injection models

These findings establish the PARK2-PGK1 axis as a critical regulator of partial epithelial-mesenchymal transition and metastasis in TNBC, suggesting that strategies to enhance PARK2 expression or activity may represent promising therapeutic approaches for this aggressive breast cancer subtype.