Inhibition of histone methyltransferase DOT1L silences ERα gene and blocks proliferation of antiestrogen-resistant breast cancer cells
Inhibition of histone methyltransferase DOT1L silences ERα gene and blocks proliferation of antiestrogen-resistant breast cancer cells
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DOI：
10.1126/sciadv.aav5590
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发表时间：
2019-02-01
期刊：
影响因子：
13.6
通讯作者：
Weisz, Alessandro
中科院分区：
文献类型：
--
作者：
Nassa, Giovanni;Salvati, Annamaria;Weisz, Alessandro
乳腺癌 (BC) 对内分泌治疗的耐药性是由持续活跃或异常的雌激素受体 α (ER α) 信号传导引起的，人们正在寻找阻断这些肿瘤中 ERa 通路的方法。我们将 H3K79 甲基转移酶 DOT1L 鉴定为 BC 细胞染色质中 ER α 的新型辅助因子，这两种蛋白质在其中共定位以调节雌激素靶基因转录。 DOT1L 阻断可减少体内和体外激素反应性 BC 细胞的增殖，从而导致细胞周期停滞和细胞凋亡，对 ER 依赖性基因转录产生广泛影响，包括 ER α 和 FOXA1 基因沉默。在小鼠异种移植物中，抗雌激素耐药的 BC 细胞也对 DOT1L 抑制作出反应，导致 ER α 水平、H3K79 甲基化和肿瘤生长降低。这些结果表明 DOT1L 是治疗内分泌治疗耐药 ER α 阳性 BC 的可利用的表观遗传靶点。
Breast cancer (BC) resistance to endocrine therapy results from constitutively active or aberrant estrogen receptor alpha (ER alpha) signaling, and ways to block ERa pathway in these tumors are sought after. We identified the H3K79 methyltransferase DOT1L as a novel cofactor of ER alpha in BC cell chromatin, where the two proteins colocalize to regulate estrogen target gene transcription. DOT1L blockade reduces proliferation of hormone-responsive BC cells in vivo and in vitro, consequent to cell cycle arrest and apoptotic cell death, with widespread effects on ER-dependent gene transcription, including ER alpha and FOXA1 gene silencing. Antiestrogen-resistant BC cells respond to DOT1L inhibition also in mouse xenografts, with reduction in ER alpha levels, H3K79 methylation, and tumor growth. These results indicate that DOT1L is an exploitable epigenetic target for treatment of endocrine therapy-resistant ER alpha-positive BCs.