Regulation of Epithelial-Mesenchymal Plasticity through Lamin A/C and EZH2 phosphorylation

Abstract

Epithelial-to-Mesenchymal Transition (EMT) and its reverse, Mesenchymal-to-Epithelial Transition (MET), underlie essential physiological processes, such as development and wound healing, while also driving pathological conditions, including cancer metastasis. While the role of chromatin regulators in EMT is well established, the contribution of nuclear structural components, particularly nuclear lamins, remains poorly understood. In this study, we demonstrate that Lamin A/C plays a pivotal role in regulating epithelial mesenchymal (E-M) plasticity through its interaction with EZH2, a key component of the Polycomb Repressive Complex 2 (PRC2). We show that overexpression of Lamin A maintains epithelial identity, whereas its depletion facilitates a mesenchymal phenotype, establishing Lamin A/C as a gatekeeper of epithelial homeostasis. Mechanistically, the phosphorylation of Lamin A/C at Ser22 and EZH2 at Thr345 by CDK1 disrupts their interaction, leading to the destabilization of EZH2. This leads to a marked reduction in H3K27me3 enrichment at the promoters of canonical EMT transcription factors, such as SNAI1, TWIST1, and ZEB1, thereby promoting mesenchymal gene expression. Conversely, expression of phospho-deficient mutants Lamin A/C (S22A) and EZH2 (T345A) stabilizes their interaction and restores epithelial features, even in EMT-inducing conditions. In vivo xenograft assays further reveal that tumorigenic potential correlates with the phosphorylation status and interaction dynamics of Lamin A/C and EZH2. Together, our findings uncover a novel nuclear structural-chromatin regulatory axis—Lamin A/C–EZH2—that governs transcriptional plasticity during EMT. This axis not only integrates the structural and epigenetic regulation of cell state transitions but also presents a potential therapeutic target for restricting metastasis in breast cancer.