Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; Merck Sharp & Dohme (UK) Limited, 120 Moorgate, London EC2M 6UR, UK.
Cell Rep. 2021 Feb 23;34(8):108776. doi: 10.1016/j.celrep.2021.108776.
Estrogen receptor-α (ER) drives tumor development in ER-positive (ER+) breast cancer. The transcription factor GATA3 has been closely linked to ER function, but its precise role in this setting remains unclear. Quantitative proteomics was used to assess changes to the ER complex in response to GATA3 depletion. Unexpectedly, few proteins were lost from the ER complex in the absence of GATA3, with the only major change being depletion of the dioxygenase TET2. TET2 binding constituted a near-total subset of ER binding in multiple breast cancer models, with loss of TET2 associated with reduced activation of proliferative pathways. TET2 knockdown did not appear to change global methylated cytosine (5mC) levels; however, oxidation of 5mC to 5-hydroxymethylcytosine (5hmC) was significantly reduced, and these events occurred at ER enhancers. These findings implicate TET2 in the maintenance of 5hmC at ER sites, providing a potential mechanism for TET2-mediated regulation of ER target genes.
雌激素受体-α（ER）驱动 ER 阳性（ER+）乳腺癌的肿瘤发生。转录因子 GATA3 与 ER 功能密切相关，但在这种情况下其确切作用仍不清楚。定量蛋白质组学用于评估 ER 复合物对 GATA3 耗竭的反应的变化。出乎意料的是，在没有 GATA3 的情况下，ER 复合物中丢失的蛋白质很少，唯一的主要变化是双加氧酶 TET2 的耗竭。TET2 结合构成了多个乳腺癌模型中 ER 结合的近全部亚基，TET2 的丢失与增殖途径的激活减少相关。TET2 敲低似乎不会改变全局甲基化胞嘧啶（5mC）水平；然而，5mC 氧化为 5-羟甲基胞嘧啶（5hmC）显著减少，这些事件发生在 ER 增强子上。这些发现表明 TET2 参与维持 ER 部位的 5hmC，为 TET2 介导的 ER 靶基因调控提供了潜在机制。
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