H3K27ac and H3K27me3 ChIP-seq analysis for MDA-MB-468 cells treated with SAHA and sonidedgib

Epigenetic therapies that cause genome-wide epigenetic alterations, could trigger local interplay between different histone marks, leading to a switch of transcriptional outcome and cellular phenotypes. In human cancers with diverse oncogenic activation, how oncogenic pathways cooperate with epigenetic modifiers to regulate the histone mark interplay is poorly understood. We herein discover that the hedgehog (Hh) pathway reprograms the histone methylation landscape in triple-negative breast cancer (TNBC), which facilitates histone acetylation caused by histone deacetylase (HDAC) inhibitors and gives rise to new therapeutic vulnerability of combination therapies. Specifically, overexpression of zinc finger protein of the cerebellum 1 (ZIC1) in TNBC promotes Hh activation, facilitating the switch of H3K27 methylation (H3K27me) to acetylation (H3K27ac). The mutually exclusive relationship of H3K27me and H3Kac allows their functional interplay at oncogenic gene locus and switches therapeutic outcomes. Using multiple in vivo TNBC models including patient-derived xenograft, we show that Hh signaling-orchestrated H3K27me and H3Kac interplay tailors combination epigenetic drugs in treating TNBC.