Phosphorylation-dependent modulation of the Lamin A/C–EZH2 complex regulates epithelial–mesenchymal plasticity

Epithelial-to-mesenchymal transition (EMT) is essential for normal development and cancer progression. However, how nuclear Lamins regulate EMT is unclear. Here, we show that Lamin A/C modulates the epithelial-mesenchymal (E-M) plasticity of cells through its interaction with the chromatin organizer, EZH2. The overexpression of Lamin A reinforces an epithelial identity, while its depletion promotes a mesenchymal phenotype. This positions Lamin A/C as a crucial modulator of Epithelial-Mesenchymal plasticity. Furthermore, CDK1-mediated phosphorylation of Lamin A/C (Ser22) and EZH2 (Thr345) disrupts Lamin A/C-EZH2 interaction, destabilizing EZH2, with a concomitant decrease in the occupancy of the heterochromatin mark (H3K27me3) on the SNAI1, TWIST1, and ZEB1 promoters, thereby facilitating a transition towards mesenchymal transcriptional programs. Conversely, phosphodeficient Lamin A/C (S22A) and EZH2 (T345A) mutants restore epithelial identity, highlighting a regulatory role of the Lamin A/C-EZH2 axis in maintaining epithelial homeostasis. In vivo, xenograft assays in NOD-SCID mice reveal that while phosphorylated Lamin A/C or EZH2 promote tumor growth and metastasis, phospho-deficient mutants markedly suppress it. Lamin A/C-EZH2 interaction regulates the expression of E-M-associated transcription factors, highlighting the role of this interaction in modulating transcriptional plasticity, thereby serving as a potential therapeutic target for regulating metastasis in breast cancers.