Nuclear receptor ESRRA promotes ERα-positive breast cancer through dual action on super enhancers and promoters to regulate gene transcriptional programs

作者：Zaozao Zheng, Lu Chen, Guo-Sheng Hu, Bing‐ling Peng, Qi-Xuan Huang, An Wang, Chuan Wang, Wen Liu · 发表于：中国科学通报：英文版 · 年份：2025 · DOI：10.1016/j.scib.2025.09.044 · 被引用次数：3 · 研究领域：Genomics and Chromatin Dynamics、Protein Degradation and Inhibitors、RNA Research and Splicing

Estrogen-Related Receptor Alpha (ESRRA) is an orphan nuclear receptor that plays a pivotal role in regulating cellular metabolism, mitochondrial biogenesis, and energy homeostasis through transcriptional control. It has been implicated in diverse physiological processes and diseases, including cancer. However, the transcriptional programs governed by ESRRA and the underlying molecular mechanisms remain incompletely understood. Here, we demonstrate that ESRRA serves as a central regulator in orchestrating the transcriptional activation of estrogen receptor α(ERα)-occupied super enhancers (ERSEs) and cognate ERα -target genes. In parallel, ESRRA represses the expression of cytosolic RNA sensors RIG1 and MDA5, thereby attenuating type I interferon (IFN) signaling and type I IFN-stimulated genes. In terms of mechanism, ESRRA is recruited to ERSEs together with ERα in response to estrogen and their binding to ERSEs occurs in a mutually dependent manner. In contrast, ESRRA directly binds to the promoter regions of RIG1 and MDA5 to suppress their expression. Consistent with these findings, pharmacological inhibition of ESRRA using its inverse agonist XCT790 suppressed estrogen/ERα-induced gene transcription while enhancing type I IFN pathway and antitumor immunity, thereby restraining ERα-positive breast cancer cell growth both in vitro and in vivo. Combination treatment with XCT790 and endocrine therapies, including the ERα antagonist Tamoxifen or degrader Fulvestrant, produced syn...