Powers Ginny L, Rajbhandari Prashant, Solodin Natalia M, Bickford Brant, Alarid Elaine T
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.
PLoS One. 2013 Dec 5;8(12):e81110. doi: 10.1371/journal.pone.0081110. eCollection 2013.
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.
雌激素受体-α（ERα）基因ESR1的表达是一种用于预测乳腺癌治疗效果的临床生物标志物。因此，人们对了解调节ESR1基因表达的机制有着浓厚的兴趣。癌症中蛋白酶体活性会增加，我们之前表明蛋白酶体抑制会导致乳腺癌细胞中ESR1基因表达丧失。乳腺癌细胞中ESR1 mRNA的表达主要通过转录起始位点（TSS）约400个碱基对（bp）内的近端启动子来控制。在这里，我们表明蛋白酶体抑制剂硼替佐米诱导的ESR1基因表达丧失与位于距TSS 150千碱基（kb）处的远端增强子失活有关。染色质免疫沉淀分析揭示了远端位点的几种硼替佐米诱导的变化，包括三种关键转录因子GATA3、FOXA1和AP2γ的占有率降低。硼替佐米治疗还导致组蛋白H3和H4乙酰化减少以及组蛋白乙酰转移酶p300的占有率降低。这些数据提示了一种机制来解释蛋白酶体抑制剂诱导的ESR1 mRNA表达丧失，该机制突出了-150 kb远端增强子处的染色质环境在调节乳腺癌细胞中ESR1基础表达中的重要性。
