KMT2D:乳腺癌表观遗传调控新靶点
  • 雌激素受体(ER)阳性乳腺癌中常见PI3KA敏感性突变,磷脂酰肌醇-(3)-激酶(PI3Ka)抑制剂促进ER依赖性转录,诱导耐药,限制其疗效;
  • 抑制PI3K使乳腺癌ER靶位染色质处于开放状态;
  • KMT2D是组蛋白H3赖氨酸4甲基转移酶,是FOXA1、PBX1和ER募集与活化所必需;
  • 抑制PI3K增强KMT2D活性,通过表观遗传学调控因子的转录后修饰控制ER活性,为ER阳性乳腺癌的表观遗传学治疗提供理论依据和全新的靶点。
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Science [IF:41.845]

PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D

PI3K通路通过表观遗传学调控因子KMT2D调控乳腺癌ER依赖性转录

10.1126/science.aah6893

2017-03-24, Report

Abstract & Authors:展开

Abstract:收起
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.

First Authors:
Hatice U Osmanbeyoglu,Pau Castel

Correspondence Authors:
Scott A Armstrong,José Baselga

All Authors:
Eneda Toska,Hatice U Osmanbeyoglu,Pau Castel,Carmen Chan,Ronald C Hendrickson,Moshe Elkabets,Maura N Dickler,Maurizio Scaltriti,Christina S Leslie,Scott A Armstrong,José Baselga

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