Abstract
<jats:p>Coffee consumption has been associated with reduced risks of multiple chronic diseases, including cancer; however, whether coffee regulates the epigenetic landscape remains largely unknown. Here, we show that coffee extensively remodels the histone acetylation landscape in human cells. Quantitative histone modification proteomics revealed a global reduction in active histone acetylation marks following coffee treatment. Mechanistically, coffee reduced the abundance of the histone acetyltransferases GCN5 and MOF, decreased 14-3-3 proteins, promoted the nuclear accumulation of class II histone deacetylases, and induced histone hypoacetylation that was reversed by the histone deacetylase inhibitor trichostatin A. Genome-wide H3K27ac profiling revealed widespread loss of promoter and enhancer acetylation, accompanied by broad transcriptional reprogramming. Integrative analyses of ChIP-seq, RNA-seq, proteomics and biochemical validation consistently demonstrated suppression of the MYC transcriptional program, including reduced MYC expression, decreased H3K27ac at MYC target promoters, downregulation of canonical MYC target genes and attenuation of MYC target gene signatures. Functionally, coffee inhibited cancer cell proliferation with minimal cell death. Collectively, our findings identify whole coffee as a previously unrecognized epigenetic modulator that remodels the histone acetylation landscape in association with suppression of the MYC transcriptional program, providing a molecular framework for understanding the epigenetic basis underlying the anti-tumor effects of coffee.</jats:p>