Dual targeting of EZH2 and Histone Deacetylases in hematological malignancies promotes transcriptional and metabolic deregulation leading to ferroptosis

The methyltransferase EZH2 functions as the enzymatic component of the PRC2 complex, which deposits methyl groups on H3K27, leading to chromatin condensation and gene repression. Recent studies have shown that EZH2 can also act as a transcriptional modulator outside of the PRC2 complex and thus, independent of its methyltransferase activity. In this study, we first aimed to investigate the effects of EZH2 enzymatic inhibition versus protein degradation in hematological malignancies. We demonstrate that EZH2 degradation is more effective in blocking cellular proliferation compared to EZH2 enzymatic inhibition, and that EZH2 targeting upregulates the cholesterol biosynthesis pathway. Secondly, combined targeting of EZH2 and HDACs showed synergistic effects in a broader spectrum of hematological malignancies. Mechanistically, combined targeting of EZH2 and HDACs induced increased levels of H3K27 acetylation and strong upregulation of cholesterol biosynthesis. This leads to metabolic stress due to acetyl-CoA depletion, ultimately inducing ferroptotic cell death.Statement of significanceWe show that combined EZH2 and HDAC targeting is a promising therapeutic strategy for a broad spectrum of hematological malignancies. We uncover that EZH2 targeting induces upregulation of cholesterol biosynthesis, which is crucial for the synergistic effect with HDAC inhibition, ultimately leading to ferroptosis induction.