权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Regulation of tumor suppression by alpha-ketoglutarate

α-酮戊二酸对肿瘤抑制的调节

基本信息

批准号：
10187535
负责人：
Lydia Finley
金额：
$ 48.92万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10187535
关键词：
Address Affect Binding Cell Differentiation process Cell Proliferation Cell Survival Chemicals Chromatin Citric Acid Cycle Consumption DNA DNA Modification Process Data Deposition Dioxygenases Down-Regulation Enzymes Epigenetic Process Family Gene Expression Gene Expression Profiling Genes Genetic Transcription Goals Growth Histones Human KRAS oncogenesis KRAS2 gene Light Maintenance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Maps Measures Mediating Metabolic Metabolic Control Metabolic Pathway Metabolism Modification Molecular Mutate Mutation Oncogenic Output Oxidases Pathologic Pathway interactions Phenocopy Precancerous Conditions Regulation Stress Succinates TP53 gene Testing Tumor Suppression Tumor Suppressor Genes Work alpha ketoglutarate cancer cell cancer initiation enzyme substrate experimental study genetic manipulation glucose metabolism histone modification inhibitor/antagonist insight malignant phenotype malignant state mouse model mutant neoplastic cell novel pancreatic cancer cells pancreatic cancer model pancreatic tumorigenesis premalignant programs response tumor tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY Many common oncogenes and tumor suppressors directly regulate metabolic pathways that support cancer cell survival, growth and proliferation. Metabolites also contribute to the regulation of the chromatin landscape: multiple cellular metabolites serve as critical co-substrates of enzymes that deposit or remove chemical modifications on histones and DNA. Oncogenic mutations in several metabolic enzymes result in the pathological accumulation of metabolites that interfere with normal maintenance of histone and DNA modifications. However, absent these specific metabolic mutations, whether the more general cancer- associated metabolic alterations driven by common oncogenes and tumor suppressors likewise affect the regulation of the chromatin landscape remains poorly understood. Using mouse models of pancreatic cancer harboring reversible expression of the tumor suppressor p53, we discovered that p53 controls levels of intracellular alpha-ketoglutarate (αKG), an obligate co-substrate of a family of αKG-dependent dioxygenases that includes the ten-eleven (TET) family of DNA methylcytosine oxidases. Restoring p53 function in malignant pancreatic cancer cells triggered intracellular αKG accumulation, which was both necessary and sufficient to increase markers of TET activity, induce tumor cell differentiation and blunt tumor progression. Our findings raise the possibility that p53-mediated accumulation of αKG and concomitant changes in the chromatin landscape and gene expression profiles contribute to the tumor suppressive function of wild-type p53. The goal of this work is to determine how wild-type p53 functions to regulate cellular αKG levels in response to oncogenic stress and how αKG contributes to p53-mediated tumor suppression. We hypothesize that regulation of metabolic pathways by p53 promotes accumulation of αKG, thereby activating gene expression programs that safeguard against malignant progression. To address this hypothesis, we will determine the mechanisms by which p53 regulates αKG (Aim 1); elucidate the pathways through which αKG induces tumor differentiation (Aim 2), and test whether αKG is a barrier to malignant progression (Aim 3). The proposed experiments will reveal how metabolic alterations that commonly occur in human tumors contribute to the maintenance of the malignant state and identify pathways that can be targeted to enforce tumor suppressive outputs even in malignant cells.

项目总结