Epigenetic regulation of chromosomal instability by EZH2 methyltransferase [CUT&RUN]

Chromosomal instability (CIN) and epigenetic alterations, major drivers of tumor evolution, contribute to breast cancer metastasis. Whether CIN is epigenetically regulated in metastatic cells is poorly understood. Here we show that EZH2 expression is highly correlated with genomic copy number alterations across human breast tumors. Consistently, increased expression of EZH2 histone methyl transferase is associated with elevated CIN in triple negative breast cancer (TNBC) metastasis initiating cells. Genetic or pharmacological inhibition of EZH2 suppresses CIN whereas forced overexpression of EZH2 in otherwise non-transformed cells promotes chromosome segregation errors. Integrated global chromatin and transcriptome profiling identified Tankyrase (TNKS), a multifunctional poly (ADP ribose) polymerase (PARP), as a direct target of EZH2 transcriptional suppressive activity. Strikingly, depletion of TNKS was sufficient to abrogate the ability of EZH2 inhibition to suppress CIN. EZH2-mediated suppression of TNKS induced centrosome amplification and multipolar mitosis which often clustered into pseudo-bipolar mitotic spindles exhibiting chromosome segregation defects. Our work establishes a previously unappreciated epigenetic regulatory mechanisms of CIN and suggests that CIN suppression might be an important component of epigenetic modifying therapies such as EZH2 inhibitors which are currently in clinical use.