Kottakis Filippos, Nicolay Brandon N, Roumane Ahlima, Karnik Rahul, Gu Hongcang, Nagle Julia M, Boukhali Myriam, Hayward Michele C, Li Yvonne Y, Chen Ting, Liesa Marc, Hammerman Peter S, Wong Kwok Kin, Hayes D Neil, Shirihai Orian S, Dyson Nicholas J, Haas Wilhelm, Meissner Alexander, Bardeesy Nabeel
Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
Nature. 2016 Nov 17;539(7629):390-395. doi: 10.1038/nature20132. Epub 2016 Oct 31.
Intermediary metabolism generates substrates for chromatin modification, enabling the potential coupling of metabolic and epigenetic states. Here we identify a network linking metabolic and epigenetic alterations that is central to oncogenic transformation downstream of the liver kinase B1 (LKB1, also known as STK11) tumour suppressor, an integrator of nutrient availability, metabolism and growth. By developing genetically engineered mouse models and primary pancreatic epithelial cells, and employing transcriptional, proteomics, and metabolic analyses, we find that oncogenic cooperation between LKB1 loss and KRAS activation is fuelled by pronounced mTOR-dependent induction of the serine-glycine-one-carbon pathway coupled to S-adenosylmethionine generation. At the same time, DNA methyltransferases are upregulated, leading to elevation in DNA methylation with particular enrichment at retrotransposon elements associated with their transcriptional silencing. Correspondingly, LKB1 deficiency sensitizes cells and tumours to inhibition of serine biosynthesis and DNA methylation. Thus, we define a hypermetabolic state that incites changes in the epigenetic landscape to support tumorigenic growth of LKB1-mutant cells, while resulting in potential therapeutic vulnerabilities.
中间代谢产生用于染色质修饰的底物，从而实现代谢状态与表观遗传状态的潜在耦合。在此，我们鉴定出一个连接代谢和表观遗传改变的网络，该网络在肝激酶B1（LKB1，也称为STK11）肿瘤抑制因子下游的致癌转化过程中起着核心作用，LKB1是营养可用性、代谢和生长的整合因子。通过构建基因工程小鼠模型和原代胰腺上皮细胞，并采用转录组学、蛋白质组学和代谢分析方法，我们发现LKB1缺失与KRAS激活之间的致癌协同作用是由丝氨酸-甘氨酸-一碳途径与S-腺苷甲硫氨酸生成的明显的mTOR依赖性诱导所驱动的。与此同时，DNA甲基转移酶上调，导致DNA甲基化增加，特别是在与转录沉默相关的逆转座子元件处富集。相应地，LKB1缺陷使细胞和肿瘤对丝氨酸生物合成抑制和DNA甲基化敏感。因此，我们定义了一种高代谢状态，这种状态会引发表观遗传格局的变化，以支持LKB1突变细胞的致瘤生长，同时导致潜在的治疗脆弱性。
