eEF2K-Mediated Stabilization of PCBP2 Promotes Oncogenic mRNA Programs in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC), characterized by the absence of effective therapeutic targets, remains a major clinical challenge with poor prognosis. The identification of novel molecular targets is therefore crucial for developing effective treatment strategies. Eukaryotic elongation factor 2 kinase (eEF2K) is highly expressed in TNBC and known to promote tumor progression; however, the precise mechanisms underlying its oncogenic role remain elusive. In this study, we identified poly(rC)-binding protein 2 (PCBP2) as a previously unrecognized downstream substrate of eEF2K. Analysis of clinical TNBC specimens revealed a positive correlation between eEF2K and PCBP2 protein expression levels. Further studies demonstrated that site-specific phosphorylation of PCBP2 at serine 189 (Ser189) markedly promoted the malignant phenotype of TNBC cells. Mechanistically, eEF2K-mediated phosphorylation at Ser189 stabilized PCBP2 by preventing its ubiquitin-proteasome-dependent degradation. This phosphorylation-dependent stabilization, in turn, enabled PCBP2 to promote the mRNA stability of pro-oncogenic genes, including TNC, SOX5, and ITGB3, thereby driving TNBC progression. Collectively, these findings not only reveal PCBP2 as a critical downstream effector of eEF2K, but also highlight the eEF2K-PCBP2 signaling axis as a promising therapeutic target for TNBC.