DUSP4 inhibited tumor cell proliferation by downregulating glycolysis via p-ERK/p-PGK1 signaling in ovarian cancer.

Abstract

Ovarian cancer (OC) remains a leading cause of gynecological cancer-related mortality, with poor prognosis and limited therapeutic options, underscoring the urgent need for a deeper understanding of OC biology. In this study, we identified a marked reduction in dual-specificity phosphatase 4 (DUSP4) expression in OC tissues compared to benign ovarian masses, with even further decreases observed in metastatic lesions. Moreover, DUSP4 expression varied among OC subtypes, with the lowest levels observed in serous ovarian cancer, and was associated with P53 and KI67 protein levels, altered TP53 mutation rates, advanced tumor stages, and poorer prognosis. Functional experiments demonstrated that DUSP4 overexpression suppressed OC cell proliferation, migration, and invasion in vitro. Phosphoproteomic profiling via LC-MS/MS analysis identified the MAPK pathway and cellular metabolism as key downstream targets of DUSP4. Notably, DUSP4 overexpression reduced phosphorylation of PGK1 at Ser203, a critical regulator of anaerobic glycolysis, and decreased its mitochondrial localization, leading to reduced lactate production and increased ROS levels. Mechanistically, DUSP4 dephosphorylated p-ERK, disrupting its interaction with PGK1 and subsequently reducing PGK1 S203 phosphorylation. In vivo, DUSP4 overexpression significantly inhibited tumor growth in mouse models, accompanied by decreased p-ERK and PGK1 S203 levels. These findings highlight a regulatory axis involving DUSP4, p-ERK, and PGK1, through which DUSP4 modulates glycolysis and tumor progression. This study establishes DUSP4 as a prognostic biomarker and a potential therapeutic target for OC, offering new insights into its role in tumor metabolism and growth.