Epigenome Remodeling Promotes Breast Cancer Recurrence and Confers Sensitivity to G9a Histone Methyltransferase Inhibitors

Primary and Recurrent tumors were analyzed by ChIP-sequencing for histone marks H3K9ac, H3K4me3, H3K27me3 and RNApol2 to characterize altered epigenetic profiles. An altered epigenetic state in recurrent tumor cells promotes sensitivity to G9a histone methyltransferase inhibitors. RNA-sequencing of two primary lines, two non-Met amplified lines, and one met-Amplified line in biological duplicate indicated that G9a inhibitor sensitivity correlates with signatures of TNF signaling. G9a inhibition reverses H3K9me2, promoting inflammatory cytokine release, and promotes p53- dependent necroptosis.