eEF1A2 promotes PTEN-GSK3β-SCF complex-dependent degradation of Aurora kinase A and is inactivated in breast cancer

Abstract

The translation elongation factor eEF1A promotes protein synthesis. Its methylation by METTL13 increases its activity, supporting tumor growth. However, in some cancers, a high abundance of eEF1A isoforms is associated with a good prognosis. Here, we found that eEF1A2 exhibited oncogenic or tumor-suppressor functions depending on its interaction with METTL13 or the phosphatase PTEN, respectively. METTL13 and PTEN competed for interaction with eEF1A2 in the same structural domain. PTEN-bound eEF1A2 promoted the ubiquitination and degradation of the mitosis-promoting Aurora kinase A in the S and G2 phases of the cell cycle. eEF1A2 bridged the interactions between the SKP1-CUL1-FBXW7 (SCF) ubiquitin ligase complex, the kinase GSK3β, and Aurora-A, thereby facilitating the phosphorylation of Aurora-A in a degron site that was recognized by FBXW7. Genetic ablation of Eef1a2 or Pten in mice resulted in a greater abundance of Aurora-A and increased cell cycling in mammary tumors, which was corroborated in breast cancer tissues from patients. Reactivating this pathway using fimepinostat, which relieves inhibitory signaling directed at PTEN and increases FBXW7 expression, combined with inhibiting Aurora-A with alisertib, suppressed breast cancer cell proliferation in culture and tumor growth in vivo. The findings demonstrate a therapeutically exploitable, tumor-suppressive role for eEF1A2 in breast cancer.

Abstract

PTEN and the translation factor eEF1A2 repress breast cancer cells.

Editor’s summary

Isoforms of the protein synthesis factor eEF1A can either promote or suppress tumor growth. Treekitkarnmongkol et al . found that eEF1A2 teams up with the tumor suppressor PTEN to repress cell cycling. The interaction between eEF1A2 and PTEN resulted in the assembly of a complex of the kinase GSK3β, the mitotic kinase Aurora-A, and the ubiquitin ligase complex SCF in the pre-mitotic phases of the cell cycle. Phosphorylation at a specific site by GSK3β marked Aurora-A for degradation by the SCF complex, reducing progression through mitosis. Accordingly, Aurora-A was more stable and abundant in PTEN-deficient breast cancers, which showed increased proliferation. A two-drug combination that derepressed PTEN and inhibited Aurora-A suppressed tumor growth in mice, suggesting a potential treatment strategy for patients with PTEN-deficient breast tumors. —Leslie K. Ferrarelli