title: The proteasome inhibitor bortezomib induces an inhibitory chromatin environment at a distal enhancer of the estrogen receptor-α gene.
abstract: Expression of the estrogen receptor-α (ERα) gene, ESR1, is a clinical biomarker used to predict therapeutic outcome of breast cancer. Hence, there is significant interest in understanding the mechanisms regulating ESR1 gene expression. Proteasome activity is increased in cancer and we previously showed that proteasome inhibition leads to loss of ESR1 gene expression in breast cancer cells. Expression of ESR1 mRNA in breast cancer cells is controlled predominantly through a proximal promoter within ∼400 base pair (bp) of the transcription start site (TSS). Here, we show that loss of ESR1 gene expression induced by the proteasome inhibitor bortezomib is associated with inactivation of a distal enhancer located 150 kilobases (kb) from the TSS. Chromatin immunoprecipitation assays reveal several bortezomib-induced changes at the distal site including decreased occupancy of three critical transcription factors, GATA3, FOXA1, and AP2γ. Bortezomib treatment also resulted in decreased histone H3 and H4 acetylation and decreased occupancy of histone acetyltransferase, p300. These data suggest a mechanism to explain proteasome inhibitor-induced loss of ESR1 mRNA expression that highlights the importance of the chromatin environment at the -150 kb distal enhancer in regulation of basal expression of ESR1 in breast cancer cells.
authors: Department of Oncology, McArdle Laboratories for Cancer Research and University of Wisconsin Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, Wisconsin, United States of America.
authors: Ginny L
authors: GL
authors: Powers
authors: Prashant
authors: P
authors: Rajbhandari
authors: Natalia M
authors: NM
authors: Solodin
authors: Brant
authors: B
authors: Bickford
authors: Elaine T
authors: ET
authors: Alarid
mesh_terms: D000107:Acetylation / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002843:Chromatin / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000187:drug effects* / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D058990:Molecular Targeted Therapy; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D001897:Boronic Acids; D002843:Chromatin; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D006657:Histones; D061988:Proteasome Inhibitors; D011719:Pyrazines; D012333:RNA, Messenger; D000069286:Bortezomib; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human