Proteasome inhibition reprograms chromatin landscape in breast cancer

Abstract

ABSTRACTThe 26S proteasome is the major protein degradation machinery in cells. Cancer cells use the proteasome to modulate gene expression networks that promote tumor growth. Proteasome inhibitors have emerged as effective cancer therapeutics, but how they work mechanistically remains unclear. Here, using integrative genomic analysis, we discovered unexpected reprogramming of the chromatin landscape and RNAPII transcription initiation in breast cancer cells treated with the proteasome inhibitor MG132. The cells acquired dynamic changes in chromatin accessibility at specific genomic loci termed Differentially Open Chromatin Regions (DOCRs). DOCRs with decreased accessibility were promoter proximal and exhibited unique chromatin architecture associated with divergent RNAPII transcription. Conversely, DOCRs with increased accessibility were primarily distal to transcription start sites and enriched in oncogenic super enhancers predominantly accessible in non-basal breast tumor subtypes. These findings describe the mechanisms by which the proteasome modulates the expression of gene networks intrinsic to breast cancer biology.HighlightsProteasome inhibition uncoversde novoDifferential Open Chromatin Regions (DOCRs) in breast cancer cells.Proteasome inhibitor sensitive promoters exhibit a distinctive chromatin architecture with discrete transcription initiation patterns.Proteasome inhibition reprograms accessibility of super enhancers.Proteasome inhibitor sensitive super enhancers distinguish basal from non-basal breast cancer subtypes.