Proteasome inhibition affects RNAPII binding. Heat maps showing differential signal for non-phosphorylated (Non-P), and serine-5 phosphorylated (Ser5P) RNAPII at DOCRs that increase (GAIN; A) and decrease (LOST; B) accessibility. Signal spans ±1 kb from the center of the DOCRs and is ranked on the basis of the degree of change in accessibility. C, Metaplots for ChIP-seq binding signals of Non-P and Ser5P RNAPII at DOCRs. Signal includes the untreated state (0) and after 4H and 24H of treatment.
ARTICLE ABSTRACT
The 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 RNA polymerase II (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 (DOCR). 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 superenhancers 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.
Our study provides a strong basis for understanding the mechanisms by which proteasome inhibitors exert anticancer effects. We find open chromatin regions that change during proteasome inhibition, are typically accessible in non-basal breast cancers.
