在乳腺癌中,PI3K通路通过表观基因调节器KMT2D调节依赖ER的转录
Eneda Toska1, Hatice U Osmanbeyoglu2, Pau Castel1,3
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
概括
在乳腺癌中向PIK3CA受到雌激素受体活性增加的限制. 这项研究显示PI3Kα抑制开放色素,通过KMT2D激活ER,这表明表观遗传疗法.
科学领域:
- 癌症学
- 分子生物学
- 表观遗传学
背景情况:
- 激活PIK3CA突变在雌激素受体 (ER) 阳性乳腺癌中很常见.
- PI3Kα抑制剂正在临床开发中,但由于补偿性ER激活,其有效性受到限制.
研究的目的:
- 研究PI3Kα抑制后驱动ER激活的基于色素的机制.
- 在PI3Kα定位时参与ER再激活的关键调节者.
主要方法:
- 使用乳腺癌模型和临床样本来分析染色体的可访问性.
- 研究KMT2D (组胺甲基转移酶) 在ER招募和激活中的作用.
- 研究了AKT,KMT2D和PI3Kα信号通路之间的相互作用.
主要成果:
- 抑制PI3Kα诱导了ER目标位点的开放色素状态.
- KMT2D对于FOXA1,PBX1和ER的招募和激活至关重要.
- 通过AKT介导的KMT2D酸化抑制了其活性,而PI3Kα抑制则增强了KMT2D活性.
结论:
- 通过涉及KMT2D的表观遗传机制,PI3Kα抑制激活ER.
- 表观遗传调节者的翻译后修饰控制了ER的激活.
- 这些发现支持开发ER阳性乳腺癌的表观遗传疗法.
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