This study investigates the pharmacological disruption of Polycomb-repressive complex 2 (PRC2)-mediated gene repression as a potential therapeutic approach for cancer treatment. The compound 3-Deazaheptanocin A (DZNep), an inhibitor of S-adenosylhomocysteine hydrolase, was found to induce apoptotic cell death in cancer cells but not in normal cells. DZNep effectively depletes PRC2 components EZH2, SUZ12, and EED, and inhibits histone H3 Lys 27 methylation. By integrating RNA interference (RNAi), genome-wide expression analysis, and chromatin immunoprecipitation (ChIP) studies, the researchers identified a set of genes selectively repressed by PRC2 in breast cancer that can be reactivated by DZNep. The reactivation of these genes, including a novel apoptosis effector FBXO32, contributes to DZNep-induced apoptosis in breast cancer cells. The results suggest that pharmacologically reversing PRC2-mediated gene repression with DZNep may represent a novel approach for cancer therapy.This study investigates the pharmacological disruption of Polycomb-repressive complex 2 (PRC2)-mediated gene repression as a potential therapeutic approach for cancer treatment. The compound 3-Deazaheptanocin A (DZNep), an inhibitor of S-adenosylhomocysteine hydrolase, was found to induce apoptotic cell death in cancer cells but not in normal cells. DZNep effectively depletes PRC2 components EZH2, SUZ12, and EED, and inhibits histone H3 Lys 27 methylation. By integrating RNA interference (RNAi), genome-wide expression analysis, and chromatin immunoprecipitation (ChIP) studies, the researchers identified a set of genes selectively repressed by PRC2 in breast cancer that can be reactivated by DZNep. The reactivation of these genes, including a novel apoptosis effector FBXO32, contributes to DZNep-induced apoptosis in breast cancer cells. The results suggest that pharmacologically reversing PRC2-mediated gene repression with DZNep may represent a novel approach for cancer therapy.