Functions of the LKB1 tumor suppressor in control in metabolism and epigenetics

细胞代谢中产生的中间产物也是共价的底物。 染色质的修饰，使代谢状态和 表观遗传控制。代谢控制和表观遗传学之间的相互作用 重新编程最近被提议作为一种潜在的机制来实现 干细胞分化的调控和癌症等病理过程的调控。我们 确定这样的网络是细胞转化下游的主要媒介 LKB1，一种重要的肿瘤抑制因子，在许多癌症中突变失活 (如肺、胰腺)。LKB1编码一种整合营养物质的丝氨酸-苏氨酸激酶 可用性、新陈代谢和生长，尽管依赖LKB1的机制 肿瘤抑制仍然难以捉摸。通过建立原代上皮细胞模型和 利用转录、蛋白质组学和代谢分析，我们发现致癌 LKB1丢失和KRAS激活之间的协同作用，变化通常是一致的 在人类癌症中，营养利用的显著改变是推波助澜的。特别是，我们 证明LKB1失活可以加强糖酵解，同时也能通畅 糖酵解中间体与丝氨酸-甘氨酸-酮碳网络偶联生成 甲基供体S-腺苷蛋氨酸(SAM)。总之，DNA甲基转移酶 (DNMT1和DNMT3A)上调，导致基因组5- 甲基胞嘧啶水平。相应地，LKB1缺乏使细胞独立于 外源丝氨酸用于生长，但对丝氨酸生物合成和抑制高度敏感 体内和体外的DNA甲基化。因此，我们定义了一种高代谢状态，导致 由于LKB1的丢失，它连接了葡萄糖代谢和染色质调节的重新连接。 这种状态既增强了LKB1的致瘤程序，也是其关键的要求。 突变细胞，为明确的患者提供新的治疗干预点 子集。在这里，我们将以这些令人兴奋的发现为基础，目标是定义这一点如何 增强的DNA甲基化有助于肿瘤表型，破译 LKB1缺失激活SGOC网络的信号和转录途径， 并进一步确定了靶向该通路在相关疾病中的治疗潜力。 活体临床前模型。

Intermediates generated in cell metabolism also serve as substrates for covalent modification of chromatin, enabling the potential coupling of metabolic states and epigenetic control. This interplay between metabolic control and epigenetic reprogramming has been recently been proposed as a potential mechanism for regulation of stem cell differentiation and for pathologic processes such as cancer. We identify such a network as a major mediator of cell transformation downstream of the LKB1, an important tumour suppressor that is mutationally inactivated in many cancers (e.g. lung, pancreas). LKB1 encodes a serine-threonine kinase that integrates nutrient availability, metabolism and growth, although the mechanisms for LKB1-dependent tumour suppression remain elusive. By developing primary epithelial cell models and employing transcriptional, proteomics, and metabolic analyses, we find that oncogenic cooperation between LKB1 loss and KRAS activation, alterations commonly coinciding in human cancer, is fueled by pronounced rewiring of nutrient utilization. In particular, we demonstrate that LKB1 inactivation potentiates glycolysis while also channeling glycolytic intermediates to the serine-glycine-one carbon network coupled to generation of the methyl donor S-adenosylmethionine (SAM). In concert, DNA methyltransferases (DNMT1 and DNMT3A) are upregulated, leading to global elevation in genomic 5- methylcytosine levels. Correspondingly, LKB1 deficiency renders cells independent of exogenous serine for growth, but highly sensitive to inhibition of serine biosynthesis and DNA methylation in vitro and in vivo. Thus, we define a hypermetabolic state resulting from loss of LKB1 that links rewiring of glucose metabolism and chromatin regulation. This state both potentiates and is critically required for the tumorigenic program of LKB1- mutant cells, suggesting novel points of therapeutic intervention in defined patient subsets. Here, we will build on these exciting findings, with the goals of defining how this enhanced DNA methylation contributes to the tumor phenotypes, deciphering the signaling and transcriptional pathways by which LKB1 loss activates to SGOC network, and further establishing the therapeutic potential of targeting this pathway in relevant in vivo preclinical models.