American Association for Cancer Research
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FIGURE 4 from Proteasome Inhibition Reprograms Chromatin Landscape in Breast Cancer

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posted on 2024-04-16, 14:20 authored by H. Karimi Kinyamu, Brian D. Bennett, James M. Ward, Trevor K. Archer

DOCR-associated TF motifs involve chromatin dynamics and cell fate. A, Heat map showing the degree of enrichment for top TFs binding motifs identified as enriched in each DOCR category. Each row corresponds to a TF. Each column corresponds to the DOCR genomic category and the heat map is split into DOCR class, Left (GAIN) and Right (LOST). B, Relative mRNA expression of TFs enriched at DOCRs, showing RNA-seq read counts in control (CTL) and 24H treated cells. C, Volcano plot showing the degree of differential binding and the statistical significance of the difference for all TF motifs queried. TF motifs with significant differential binding are colored red (increase) and blue (decrease). D, Relative mRNA expression of TFs identified by TOBIAS, showing RNA-seq read counts in control (CTL) and 24H treated cells. E, Dot plot showing the degree of enrichment for gene lists enriched with genes closest to DOCRs split by category. Dot size represents the number of genes in each Gene Ontology (GO) biological processes.

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HHS | NIH | National Institute of Environmental Health Sciences (NIEHS)

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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.