LKB1 损失将血清代谢与 DNA 甲基化和瘤产生联系起来
Filippos Kottakis1,2,3, Brandon N Nicolay1,3, Ahlima Roumane1,2,3
1Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
Nature
|November 4, 2016
概括
通过改变新陈代谢和表观遗传学, 这为向性治疗创造了脆弱性,为LKB1突变癌症提供了新的治疗策略.
科学领域:
- 癌症学
- 代谢途径
- 表观遗传学
背景情况:
- 介质代谢为染色质修饰提供基质,将代谢和表观遗传状态联系起来.
- 肝激酶B1 (LKB1/STK11) 瘤抑制剂整合了营养的可用性,新陈代谢和生长.
- LKB1损失与瘤转化有关.
研究的目的:
- 在LKB1缺陷癌症中确定代谢和表观遗传变化的联系网络.
- 研究氨酸-甘氨酸-一碳路径和S-adenosylmethionine在LKB1突变瘤发生中的作用.
- 探索与这种代谢-表观遗传重编相关的治疗脆弱性.
主要方法:
- 基因工程小鼠模型和主要的胰腺上皮细胞.
- 转录,蛋白质组和代谢分析.
- 研究DNA甲基转移酶和逆转移素甲基化.
主要成果:
- 与KRAS激活相结合的LKB1损失会诱导一种mTOR依赖的氨酸- 一碳路径,增加S- 腺甲.
- DNA甲基转移酶的升级导致DNA甲基化增加,特别是在逆转移子.
- 缺乏LKB1的细胞和瘤对抑制血清生物合成和DNA甲基化具有敏感性.
结论:
- 由LKB1损失驱动的高代谢状态改变了表观遗传环境,促进了瘤发生.
- 这种代谢-表观遗传重编程在LKB1突变癌症中造成治疗漏洞.
- 向血清生物合成或DNA甲基化可能是有效的治疗策略.
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