Histone Methylation and Epigenetic Silencing in Breast Cancer

Abstract : This research was to investigate the role of a chromatin-modifying enzyme, called EZH2, in breast cancer epigenetics and to develop strategies to identify chemical inhibitors of this enzyme. EZH2 is a histone methyltransferase which modifies lysine-27 of histone H3, an epigenetic mark linked to gene silencing and implicated in tumor suppressor silencing during breast cancer progression. Progress on this project included: 1) Identification of target genes directly silenced by EZH2 in breast cancer cells, 2) Mapping of EZH2 association within the chromatin of one such target gene, 3) Demonstration that a DNA-binding protein, called YY1, co-localizes at this target chromatin, and 4) Evidence that YY1 is needed for silencing and EZH2 chromatin binding at this target gene. These results suggest that YY1 binding sites help define response elements that recruit and mediate EZH2 silencing in breast cancer cells. The defined EZH2 response element was evaluated for use in developing a breast cancer cell-based bioassay to screen for EZH2 inhibitors. These inhibitors provide important drug compounds to test as part of emerging epigenetic therapies to combat cancer.