PI3K経路は,KMT2Dというエピジェネティックレギュレータを通して,乳がんにおけるER依存トランスクリプションを調節する
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.
Science (New York, N.Y.)
|March 25, 2017
まとめ
乳がんにおけるPIK3CAの標的化は,エストロゲン受容体の活性が増加することで制限されます. この研究では,PI3Kαの阻害がクロマチンを開き,KMT2D経由でERを活性化させ,エピジェネティック療法を示唆しています.
科学分野:
- 腫瘍学
- 分子生物学
- エピジェネティクス
背景:
- エストロゲン受容体 (ER) 陽性乳がんでは,PIK3CAを活性化する変異が一般的です.
- PI3Kα阻害剤は臨床開発中ですが,補償的なER活性化により有効性の制限に直面しています.
研究 の 目的:
- PI3Kα阻害後のER活性化を誘発するクロマチンベースのメカニズムを調査する.
- PI3Kαターゲティング時にER再活性化に関与する重要なレギュレータを特定する.
主な方法:
- クロマチンのアクセシビリティを分析するために,乳がんモデルと臨床サンプルを使用した.
- ERの募集と活性化におけるKMT2D (ヒストンメチルトランスファーゼ) の役割を調査した.
- AKT,KMT2D,PI3Kαの信号伝達経路の相互作用を調べました.
主要な成果:
- PI3Kαの阻害により,ERの標的部位でオープンクロマチンの状態が誘発された.
- KMT2DはFOXA1,PBX1,ERの募集と活性化に不可欠でした.
- KMT2Dの活性が抑制され,PI3Kαの抑制はKMT2Dの活性が強化された.
結論:
- PI3Kαの抑制は,KMT2Dを含む表遺伝的メカニズムを通じてERを活性化します.
- エピジェネティック・レギュレータの翻訳後の変化が ERの活性化を制御する.
- これらの発見は,ER陽性乳がんのエピジェネティック療法の開発を支援します.
関連する概念動画
01:22PI3K/mTOR/AKT Signaling Pathway
6.0K
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a...
6.0K
03:03mTOR Signaling and Cancer Progression
5.0K
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
5.0K
02:23Abnormal Proliferation
5.3K
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
5.3K
01:46Epigenetic Regulation
34.1K
Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
34.1K
01:37Epigenetic Regulation
4.0K
Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
X-chromosome...
X-chromosome...
4.0K
02:23Master Transcription Regulators
7.9K
Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
7.9K