Estrogen receptor α (ER) acts as an oncogenic signal in endometrial endometrioid carcinoma. ER binding activity largely depends on chromatin remodeling and recruitment of transcription factors to estrogen response elements. A deeper understanding of these regulatory mechanisms may uncover therapeutic targets for ER-dependent endometrial cancers. We show that estrogen induces accessible chromatin and ER binding at a subset of enhancers, which form higher-order super enhancers that are vital for ER signaling. ER positively correlates with active enhancers in primary tumors, and tumors were effectively classified into molecular subtypes with chromatin accessibility dynamics and ER-dependent gene signature. ARID1A binds within ER-bound enhancers and regulates ER-dependent transcription. Knockdown of ARID1A or fulvestrant treatment profoundly affects the gene-expression program, and inhibits cell growth phenotype by affecting the chromatin environment. Importantly, we found dysregulated expression of circadian rhythms genes by estrogen in cancer cells and in primary tumors. Knockdown of ARID1A reduces the chromatin accessibility and ER binding at enhancers of the circadian gene ARNTL and BHLHE41, leading to a decreased expression of these genes. Altogether, we uncover a critical role for ARID1A in ER signaling and therapeutic target in ER-positive endometrial cancer.

雌激素受体 α (ER) 在子宫内膜子宫内膜样癌中充当致癌信号。 ER 结合活性很大程度上取决于染色质重塑和转录因子向雌激素反应元件的募集。更深入地了解这些调节机制可能会发现 ER 依赖性子宫内膜癌的治疗靶点。我们发现雌激素在增强子的子集上诱导可接近的染色质和 ER 结合，这些增强子形成对 ER 信号转导至关重要的高阶超级增强子。 ER 与原发性肿瘤中的活性增强子呈正相关，并且肿瘤被有效地分类为具有染色质可及性动态和 ER 依赖性基因特征的分子亚型。 ARID1A 与 ER 结合增强子结合并调节 ER 依赖性转录。 ARID1A 的敲低或氟维司群治疗会深刻影响基因表达程序，并通过影响染色质环境来抑制细胞生长表型。重要的是，我们发现癌细胞和原发性肿瘤中雌激素导致昼夜节律基因表达失调。 ARID1A 的敲除降低了昼夜节律基因 ARNTL 和 BHLHE41 增强子处的染色质可及性和 ER 结合，导致这些基因的表达减少。总而言之，我们发现 ARID1A 在 ER 阳性子宫内膜癌的 ER 信号传导和治疗靶点中发挥关键作用。