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

LKB1肿瘤抑制因子在代谢和表观遗传学控制中的功能

基本信息

  • 批准号:
    10524240
  • 负责人:
  • 金额:
    $ 11.65万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-01-01 至 2023-12-31
  • 项目状态:
    已结题

项目摘要

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.
细胞代谢过程中产生的中间体也作为共价的底物

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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NABEEL El-BARDEESY其他文献

NABEEL El-BARDEESY的其他文献

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{{ truncateString('NABEEL El-BARDEESY', 18)}}的其他基金

Functions of mutant IDH in cholangiocarcinoma
突变IDH在胆管癌中的功能
  • 批准号:
    10800231
  • 财政年份:
    2023
  • 资助金额:
    $ 11.65万
  • 项目类别:
2023 Pancreatic Diseases Gordon Research Conference and Gordon Research Seminar
2023年胰腺疾病戈登研究大会暨戈登研究研讨会
  • 批准号:
    10681581
  • 财政年份:
    2023
  • 资助金额:
    $ 11.65万
  • 项目类别:
Mechanistic Understanding for the Role of Lin28b in Pancreatic Cancer Progression
Lin28b 在胰腺癌进展中作用的机制理解
  • 批准号:
    10558954
  • 财政年份:
    2019
  • 资助金额:
    $ 11.65万
  • 项目类别:
Mechanistic Understanding for the Role of Lin28b in Pancreatic Cancer Progression
Lin28b 在胰腺癌进展中作用的机制理解
  • 批准号:
    10338071
  • 财政年份:
    2019
  • 资助金额:
    $ 11.65万
  • 项目类别:
Mechanistic Understanding for the Role of Lin28b in Pancreatic Cancer Progression
Lin28b 在胰腺癌进展中作用的机制理解
  • 批准号:
    10559707
  • 财政年份:
    2019
  • 资助金额:
    $ 11.65万
  • 项目类别:
Mechanistic Understanding for the Role of Lin28b in Pancreatic Cancer Progression
Lin28b 在胰腺癌进展中作用的机制理解
  • 批准号:
    10738337
  • 财政年份:
    2019
  • 资助金额:
    $ 11.65万
  • 项目类别:
Targeting novel therapeutic vulnerabilities in LKB1 mutant tumors.
针对 LKB1 突变肿瘤的新治疗漏洞。
  • 批准号:
    10443802
  • 财政年份:
    2018
  • 资助金额:
    $ 11.65万
  • 项目类别:
Functions of the LKB1 tumor suppressor in control in metabolism and epigenetics
LKB1肿瘤抑制因子在代谢和表观遗传学控制中的功能
  • 批准号:
    10337194
  • 财政年份:
    2018
  • 资助金额:
    $ 11.65万
  • 项目类别:
Targeting novel therapeutic vulnerabilities in LKB1 mutant tumors.
针对 LKB1 突变肿瘤的新治疗漏洞。
  • 批准号:
    10208803
  • 财政年份:
    2018
  • 资助金额:
    $ 11.65万
  • 项目类别:
Functions of the LKB1 tumor suppressor in control in metabolism and epigenetics
LKB1肿瘤抑制因子在代谢和表观遗传学控制中的功能
  • 批准号:
    10083201
  • 财政年份:
    2018
  • 资助金额:
    $ 11.65万
  • 项目类别:

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骨骼合成代谢过程中骨-脂肪相互作用
  • 批准号:
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  • 财政年份:
    2022
  • 资助金额:
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  • 项目类别:
Bone-Adipose Interactions During Skeletal Anabolism
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  • 批准号:
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  • 财政年份:
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  • 批准号:
    10365254
  • 财政年份:
    2021
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    $ 11.65万
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Bone-Adipose Interactions During Skeletal Anabolism
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促进NAD合成代谢以延长寿命
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    $ 11.65万
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