Epigenetic regulation of chromosomal instability by EZH2 methyltransferase.

Chromosomal instability (CIN) and epigenetic reprogramming are central drivers of breast cancer progression, yet the mechanisms connecting them remain elusive. We uncover a direct role of EZH2 histone methyltransferase in promoting CIN in triple-negative breast cancer (TNBC). Across breast cancers, EZH2 expression correlates with copy number alterations, and its catalytic activity is associated with increased CIN in metastasis-initiating cells. Pharmacological EZH2 inhibition suppressed CIN, revealing an unexpected vulnerability. Integrated chromatin and transcriptome profiling identified Tankyrase (TNKS), a poly(ADP-ribose) polymerase, as a direct transcriptional target of EZH2. Mechanistically, EZH2-mediated TNKS suppression disrupts CPAP (centrosomal P4.1-associated protein), driving centrosome overduplication, multipolar mitosis and exacerbated CIN. In vivo, CIN suppression is a critical mechanism underlying the anti-metastatic effects of EZH2 inhibition. These findings delineate a previously unrecognized epigenetic mechanism governing CIN and establish EZH2 inhibitors as the first therapeutic agents capable of directly suppressing CIN, underscoring the need for trials with metastasis-focused endpoints.