Epigenetic regulation of chromosomal instability by EZH2 methyltransferase.

Abstract

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.