The role of ACSS2 in colon cancer

ACSS2 在结肠癌中的作用

• 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
• 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

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.

人结直肠癌（CRC）和CRC小鼠模型的分析揭示了在大肠癌中， 介导短链脂肪酸（SCFA）代谢的酶，包括ACSS 2。与许多其他癌症不同， ACSS2低表达与CRC进展相关，并预测无病生存率低。ACSS2 从醋酸盐中产生细胞质和细胞核乙酰CoA，用于从头脂质合成并驱动基因座特异性 组蛋白乙酰化促进基因表达。实验性增加人CRC细胞中的ACSS2限制 在软琼脂中的克隆形成和生长，与ACSS2抑制肿瘤发生一致。 结肠肿瘤在独特的代谢环境中发展，其中肠道细菌产生高水平的 SCFA，包括乙酸盐和丁酸盐。正常结肠上皮细胞依赖于细菌SCFA，主要是丁酸盐， 他们的能源需求。与ACSS 2一样，丁酸代谢酶，包括ACSM 3和ACADS， 在结直肠癌中表达下调，并且低表达与较差的存活相关。我们发现，增加ACSM 3 表达降低了人CRC细胞系的增殖，并且自发缺失ACADS的小鼠 对致癌物诱发的结肠腺瘤更敏感。因此，我们的初步数据支持一个模型， ACSS2和丁酸代谢酶限制肿瘤发生，特别是在结肠。 我们的总体假设是ACSS2低表达通过组蛋白乙酰化降低促进CRC 以及其靶基因的表达，包括那些编码丁酸代谢的基因。这有助于切换 从SCFA代谢到肿瘤中的糖酵解。然而，它也产生了癌症特有的脆弱性， 由此具有低ACSS 2的CRC细胞在其产生用于组蛋白乙酰化的乙酰CoA的能力方面受损， 从头脂质合成。我们建议利用这种肿瘤特异性的脆弱性，通过靶向乙酰基 CoA合成与依赖于ACSS2介导的组蛋白乙酰化的核过程。 三个目标将解决我们的总体假设：1）我们将使用小鼠模型、人CRC细胞系和人大肠癌细胞系。 以测试ACSS2和ACADS是否抑制原发性结肠肿瘤和转移。2)我们将测试如果 ACSS2通过控制基因座特异性组蛋白乙酰化来限制CRC，如果ACSS2驱动丁酸代谢基因， 表达以增加丁酸盐的使用并抑制糖酵解。3)我们将检验低ACSS 2水平 使结肠肿瘤对靶向依赖于ACSS2的染色质模板功能的疗法敏感。 这项工作将阐明ACSS2在CRC中的一种新的肿瘤抑制功能，确定ACSS2如何在CRC中发挥作用。 控制代谢，并确定CRC的新治疗方法。