The role of ACSS2 in colon cancer

ACSS2 在结肠癌中的作用

基本信息

批准号：
10593172
负责人：
TODD W BAUER
金额：
$ 46.14万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593172
关键词：
Acceleration Acetates Acetyl Coenzyme A Acetylation Agar Anchorage-Independent Growth Binding Butyrates Cancer Model Carcinogens Cells Chromatin Citrates Coenzyme A Ligases Colon Colon Carcinoma Colonic Adenoma Colonic Neoplasms Colorectal Cancer Control Locus DNA Damage Data Disease-Free Survival Disseminated Malignant Neoplasm Environment Enzymes Epigenetic Process Epithelium Gene Expression Genes Genetic Transcription Glycolysis Glycolysis Inhibition Growth Histone Acetylation Human Impairment Left Link Lipids Malignant Neoplasms Mediating Metabolic Metabolic Control Metabolism Mitochondria Modeling Mus Neoplasm Metastasis Nuclear Phenotype Predisposition Process Production Proliferating Protein Acetylation Role Source Testing Therapeutic Transferase Tumor Burden Tumor stage Volatile Fatty Acids Work Xenograft Model Xenograft procedure cancer cell chemical carcinogen colon cancer cell line colon cancer patients colon cancer progression colon tumorigenesis colorectal cancer progression combinatorial fatty acid metabolism gut bacteria gut microbiota mouse model mutant neoplastic cell novel novel therapeutic intervention novel therapeutics programs recruit restraint targeted treatment therapeutic target tumor tumor progression tumorigenesis tumorigenic

项目摘要

Analysis of human colorectal cancer (CRC) and mouse models of CRC reveals decreased expression of enzymes that mediate short chain fatty acid (SCFA) metabolism, including ACSS2. Unlike in many other cancers, low ACSS2 expression is associated with CRC progression, and predicts poor disease-free survival. ACSS2 generates cytosolic and nuclear acetyl CoA from acetate for de novo lipid synthesis and drives locus-specific histone acetylation to promote gene expression. Experimentally increasing ACSS2 in human CRC cells limits clonogenicity and growth in soft agar, consistent with ACSS2 restraining tumorigenesis. Colon tumors develop in a unique metabolic environment, in which gut bacteria generate high levels of SCFAs, including acetate and butyrate. Normal colon epithelia rely on bacterial SCFAs, primarily butyrate, for their energy needs. As with ACSS2, butyrate metabolic enzymes, including ACSM3 and ACADS, are downregulated in CRC, and low expression correlates with poor survival. We show that increasing ACSM3 expression reduces proliferation in human CRC cell lines, and that mice with a spontaneous deletion of ACADS are more susceptible to carcinogen induced colon adenomas. Thus, our preliminary data support a model in which ACSS2 and butyrate metabolic enzymes limit tumorigenesis specifically in the colon. Our overall hypothesis is that low ACSS2 expression promotes CRC via decreased histone acetylation and expression of its target genes, including those that encode butyrate metabolism. This facilitates a switch from SCFA metabolism to glycolysis in the tumor. However, it also creates a cancer-specific vulnerability, whereby CRC cells with low ACSS2 are impaired in their ability generate acetyl CoA for histone acetylation and de novo lipid synthesis. We propose to exploit this tumor-specific vulnerability therapeutically by targeting acetyl CoA synthesis together with nuclear processes that depend on ACSS2-mediated histone acetylation. Three Aims will address our overall hypothesis: 1) We will use mouse models, human CRC cell lines and xenografts to test if ACSS2 and ACADS restrain both primary colon tumors and metastases. 2) We will test if ACSS2 limits CRC by controlling locus-specific histone acetylation, and if ACSS2 drives butyrate metabolic gene expression to increase butyrate use and inhibit glycolysis. 3) We will test the hypothesis that low ACSS2 levels sensitize colon tumors to therapies targeting chromatin-templated functions that depend on ACSS2. This work will elucidate a novel tumor restraint function for ACSS2 in CRC, determine how ACSS2 controls metabolism, and identify new therapeutic approaches for CRC.

人类结直肠癌（CRC）和CRC小鼠模型的分析显示，介导短链脂肪酸（SCFA）代谢的酶，包括ACSS2。与许多其他癌症不同，低ACSS2表达与CRC的进展有关，并预测无病生存不良。 ACSS2 从乙酸乙酸酯中生成胞质和核乙酰基COA，以从头脂质合成并驱动特定于基因座的特异性组蛋白乙酰化以促进基因表达。实验增加人CRC细胞中的ACSS2限制软琼脂中的克隆原性和生长，与ACSS2约束肿瘤发生一致。结肠肿瘤在独特的代谢环境中发展，其中肠道细菌会产生高水平的 SCFA，包括乙酸盐和丁酸酯。正常结肠上皮依赖于细菌SCFA，主要是丁酸酯，因为他们的能量需求。与ACS2一样，丁酸酯代谢酶（包括ACSM3和Acads）是在CRC中下调，低表达与存活不良相关。我们表明ACSM3增加表达降低了人CRC细胞系中的增殖，而小鼠自发缺失了更容易受到致癌诱导的结肠腺瘤的影响。因此，我们的初步数据支持模型 ACSS2和丁酸代谢酶专门在结肠中限制了肿瘤发生。我们的总体假设是，低ACSS2表达通过减少组蛋白乙酰化促进CRC 其靶基因的表达，包括编码丁酸代谢的基因。这有助于开关从SCFA代谢到肿瘤中的糖酵解。但是，它也会产生特定于癌症的脆弱性，因此，具有低ACS2的CRC细胞的能力受损会产生用于组蛋白乙酰化的乙酰基COA和从头脂质合成。我们建议通过靶向乙酰基来治疗这种肿瘤特异性脆弱性 COA合成以及依赖ACSS2介导的组蛋白乙酰化的核过程。三个目标将解决我们的整体假设：1）我们将使用鼠标模型，人类CRC细胞系和异种移植物测试ACSS2和ACAD是否抑制原发性结肠肿瘤和转移酶。 2）我们将测试是否 ACSS2通过控制基因座特异性组蛋白乙酰化来限制CRC，如果ACSS2驱动丁酸酯代谢基因表达增加丁酸酯的使用并抑制糖酵解。 3）我们将测试较低的ACSS2水平的假设将结肠肿瘤敏感到靶向取决于ACSS2的染色质型功能的疗法。这项工作将阐明CRC中ACSS2的新型肿瘤约束功能，确定ACSS2如何控制新陈代谢，并确定CRC的新治疗方法。