PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D.
PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D.
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DOI：
10.1126/science.aah6893
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发表时间：
2017-03-24
期刊：
影响因子：
--
通讯作者：
Baselga J
中科院分区：
文献类型：
--
作者：
Toska E;Osmanbeyoglu HU;Castel P;Chan C;Hendrickson RC;Elkabets M;Dickler MN;Scaltriti M;Leslie CS;Armstrong SA;Baselga J
在雌激素受体(ER)阳性的乳腺癌中，经常发现编码磷脂酰肌醇-激酶α(PI3Kα)的基因PIK3CA的激活突变。PI3Kα抑制剂目前处于临床开发的晚期，可诱导ER依赖的转录强劲代偿性增加，从而限制治疗效果。我们研究了PI3Kα抑制后导致ER激活的基于染色质的机制。我们发现，在乳腺癌模型和临床样本中，PI3Kα抑制介导了ER靶点的开放染色质状态。KMT2D是一种组蛋白H3赖氨酸4甲基转移酶，是FOXA1、Pbx1和ER募集和激活所必需的。AKT结合并磷酸化KMT2D，减弱甲基转移酶活性和内质网功能，而抑制PI3Kα则增强KMT2D活性。这些发现揭示了一种通过表观遗传调节因子的翻译后修饰来控制ER激活的机制，为ER阳性乳腺癌的表观遗传治疗提供了理论基础。
Activating mutations in PIK3CA, the gene encoding phosphoinositide--kinase α (PI3Kα), are frequently found in estrogen receptor (ER)–positive breast cancer. PI3Kα inhibitors, now in late-stage clinical development, elicit a robust compensatory increase in ER-dependent transcription that limits therapeutic efficacy. We investigated the chromatin-based mechanisms leading to the activation of ER upon PI3Kα inhibition. We found that PI3Kα inhibition mediates an open chromatin state at the ER target loci in breast cancer models and clinical samples. KMT2D, a histone H3 lysine 4 methyltransferase, is required for FOXA1, PBX1, and ER recruitment and activation. AKT binds and phosphorylates KMT2D, attenuating methyltransferase activity and ER function, whereas PI3Kα inhibition enhances KMT2D activity. These findings uncover a mechanism that controls the activation of ER by the posttranslational modification of epigenetic regulators, providing a rationale for epigenetic therapy in ER-positive breast cancer.