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PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D
Science ( IF 56.9 ) Pub Date : 2017-03-23 , DOI: 10.1126/science.aah6893
Eneda Toska 1 , Hatice U Osmanbeyoglu 2 , Pau Castel 1, 3 , Carmen Chan 1 , Ronald C Hendrickson 4 , Moshe Elkabets 1, 5 , Maura N Dickler 6 , Maurizio Scaltriti 1, 7 , Christina S Leslie 2 , Scott A Armstrong 8, 9 , José Baselga 1, 6
Affiliation  

Tumor cells develop resistance to a drug used to treat breast cancer through a chromatin remodeling mechanism. Chromatin state dictates drug response Drugs inhibiting the phosphoinositide-(3)-kinase (PI3K) signaling pathway are effective in a subset of breast cancer patients. Tumors become resistant to these drugs, however, and this transition is often accompanied by increased transcription of genes regulated by the estrogen receptor. A better understanding of the mechanism linking PI3K signaling and estrogen receptor activity could potentially suggest strategies to prevent drug resistance. Toska et al. found that PI3K inhibition activates a specific epigenetic regulator, the histone methyltransferase KMT2D. The protein modifications catalyzed by KMT2D create a more open chromatin state, which unleashes estrogen receptor–dependent transcription. Thus, combination therapies consisting of PI3K inhibitors and KMT2D inhibitors may be more effective than PI3K inhibitors alone. Science, this issue p. 1324 Activating mutations in PIK3CA, the gene encoding phosphoinositide-(3)-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.

中文翻译:

PI3K 通路通过表观遗传调节因子 KMT2D 调节乳腺癌中 ER 依赖性转录

肿瘤细胞通过染色质重塑机制对治疗乳腺癌的药物产生耐药性。染色质状态决定药物反应 抑制磷酸肌醇-(3)-激酶 (PI3K) 信号通路的药物对部分乳腺癌患者有效。然而,肿瘤对这些药物产生耐药性,并且这种转变通常伴随着雌激素受体调节的基因转录的增加。更好地了解 PI3K 信号传导和雌激素受体活性之间的联系机制可能会提出预防耐药性的策略。托斯卡等人。研究发现,PI3K 抑制会激活特定的表观遗传调节因子,即组蛋白甲基转移酶 KMT2D。KMT2D 催化的蛋白质修饰创造了更开放的染色质状态,从而释放雌激素受体依赖性转录。因此,由 PI3K 抑制剂和 KMT2D 抑制剂组成的联合疗法可能比单独使用 PI3K 抑制剂更有效。科学,本期第 14 页。1324 PIK3CA(编码磷酸肌醇-(3)-激酶 α (PI3Kα) 的基因)的激活突变常见于雌激素受体 (ER) 阳性乳腺癌中。PI3Kα 抑制剂目前正处于临床开发后期,会引起 ER 依赖性转录的强烈代偿性增加,从而限制了治疗效果。我们研究了 PI3Kα 抑制时导致 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 抑制可介导 ER 靶位点处的开放染色质状态。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 ER 功能,而 PI3Kα 抑制则增强 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。
更新日期:2017-03-23
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