Targeting EZH2 and HDACs in hematological cancers induces transcriptional and metabolic deregulation causing 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, independently of the PRC2 complex and its methyltransferase activity. In this study, we demonstrate that EZH2 degradation is more effective in blocking cellular proliferation compared to EZH2 enzymatic inhibition. Strikingly, the combination of EZH2 degradation and HDAC inhibition exhibited potent synergy in a broad spectrum of hematological malignancies. The dual inhibition led to increased H3K27 acetylation and transcriptional deregulation, revealing that the observed synergy is driven by metabolic reprogramming. A metabolism-centered analysis showed upregulation of cholesterol biosynthesis in several hematological malignancies upon combined inhibition of EZH2 and HDACs. Interestingly, EZH2 degradation and HDAC inhibition also independently modulate distinct metabolic pathways: EZH2 degradation enhances fatty acid biosynthesis, while HDAC inhibition activates the tricarboxylic acid (TCA) cycle. The overactivation of cholesterol and fatty acid synthesis, of the TCA cycle, and histone hyperacetylation, strongly suggests induction of metabolic stress. Indeed, as a result of EZH2 degradation and HDAC inhibition, we observed an increase of reactive oxygen species (ROS), promoting lipid peroxidation and ultimately triggering ferroptotic cell death. Together, our findings highlight that co-targeting EZH2 and HDAC leads to an increase of histone acetylation and the overactivation of several metabolic pathways, leading to strong metabolic stress and induction of ferroptotic cell death.