ARID1A-dependent permissive chromatin accessibility licenses estrogen-receptor signaling to regulate circadian rhythms genes in endometrial cancer
ARID1A-dependent permissive chromatin accessibility licenses estrogen-receptor signaling to regulate circadian rhythms genes in endometrial cancer
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ARID1A依赖性允许染色质可及性许可雌激素受体信号传导来调节子宫内膜癌中的昼夜节律基因
DOI：
10.1016/j.canlet.2020.08.034
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发表时间：
2020
期刊：
影响因子：
9.7
通讯作者：
Lin Wang
中科院分区：
文献类型：
--
作者：
Hanyang Hu;Zhiguo Chen;Lulu Ji;Yanling Wang;Mengzhen Yang;Rujie Lai;Yu Zhong;Xiaoli Zhang;Lin Wang
雌激素受体α (ER)在子宫内膜样癌中起着致癌信号的作用。内质网结合活性很大程度上取决于染色质重塑和雌激素反应元件转录因子的募集。对这些调控机制的深入了解可能会揭示er依赖性子宫内膜癌的治疗靶点。我们发现雌激素诱导可接近的染色质和内质网结合在一个子集的增强子，形成高阶超级增强子，是至关重要的内质网信号。在原发肿瘤中，ER与活性增强子正相关，并根据染色质可及性动力学和ER依赖基因特征有效地将肿瘤划分为分子亚型。ARID1A结合er结合增强子并调节er依赖性转录。敲低ARID1A或氟维司汀治疗会深刻影响基因表达程序，并通过影响染色质环境抑制细胞生长表型。重要的是，我们在癌细胞和原发性肿瘤中发现了雌激素对昼夜节律基因表达的失调。ARID1A的敲低降低了昼夜节律基因ARNTL和BHLHE41增强子的染色质可及性和内质网结合，导致这些基因的表达减少。总之，我们揭示了ARID1A在ER阳性子宫内膜癌的ER信号传导和治疗靶点中的关键作用。
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.