Figure 6. Model of ESR1 regulation by proteasome inhibitors.

Under basal conditions in the absence of estrogen, the ESR1 distal enhancer is acetylated on histones H3 and H4, and is occupied by FOXA1, AP2γ, GATA3, p300 and RNA PolII. Histone H3 and H4 are also acetylated on the proximal promoter which is occupied by RNA PolII and AP2γ. After the addition of bortezomib, the distal enhancer exhibits decreased histone acetylation and increased histone methylation. Occupancy of FOXA1, AP2γ, GATA3, p300 and RNA PolII decreases on the distal enhancer. In contrast, histone acetylation, methylation, and AP2γ occupancy on the proximal promoter are unchanged, but RNA PolII occupancy decreases. These data support a model where bortezomib-induced changes in the chromatin environment around the distal enhancer regulate ESR1 expression in ER+ breast cancer cells.