Yang Feng, Ma Qi, Liu Zhijie, Li Wenbo, Tan Yuliang, Jin Chunyu, Ma Wubin, Hu Yiren, Shen Jia, Ohgi Kenneth A, Telese Francesca, Liu Wen, Rosenfeld Michael G
Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Mol Cell. 2017 May 4;66(3):321-331.e6. doi: 10.1016/j.molcel.2017.03.019.
The molecular mechanisms underlying the opposing functions of glucocorticoid receptors (GRs) and estrogen receptor α (ERα) in breast cancer development remain poorly understood. Here we report that, in breast cancer cells, liganded GR represses a large ERα-activated transcriptional program by binding, in trans, to ERα-occupied enhancers. This abolishes effective activation of these enhancers and their cognate target genes, and it leads to the inhibition of ERα-dependent binding of components of the MegaTrans complex. Consistent with the effects of SUMOylation on other classes of nuclear receptors, dexamethasone (Dex)-induced trans-repression of the estrogen E program appears to depend on GR SUMOylation, which leads to stable trans-recruitment of the GR-N-CoR/SMRT-HDAC3 corepressor complex on these enhancers. Together, these results uncover a mechanism by which competitive recruitment of DNA-binding nuclear receptors/transcription factors in trans to hot spot enhancers serves as an effective biological strategy for trans-repression, with clear implications for breast cancer and other diseases.
糖皮质激素受体（GRs）和雌激素受体α（ERα）在乳腺癌发展过程中发挥相反作用的分子机制仍未得到充分了解。在此，我们报告，在乳腺癌细胞中，配体结合的GR通过反式结合到ERα占据的增强子上，抑制了一个由ERα激活的大型转录程序。这消除了这些增强子及其同源靶基因的有效激活，并导致对MegaTrans复合物成分的ERα依赖性结合的抑制。与SUMO化对其他类核受体的作用一致，地塞米松（Dex）诱导的雌激素E程序的反式抑制似乎依赖于GR SUMO化，这导致GR-N-CoR/SMRT-HDAC3共抑制复合物在这些增强子上的稳定反式募集。这些结果共同揭示了一种机制，即DNA结合核受体/转录因子通过反式竞争性募集到热点增强子上，作为一种有效的反式抑制生物学策略，这对乳腺癌和其他疾病具有明确的意义。
