The role of ACSS2 in colon cancer

对人类结直肠癌(CRC)和小鼠结直肠癌模型的分析显示， 调节短链脂肪酸(SCFA)代谢的酶，包括ACSS2。与许多其他癌症不同， ACSS2的低表达与CRC的进展有关，并预示着较差的无病生存率。ACSS2 从醋酸盐产生胞浆和核乙酰辅酶A，用于从头合成脂质，并驱动基因位点特异性 组蛋白乙酰化促进基因表达。实验性增加人结直肠癌细胞ACSS2的极限 在软琼脂中的克隆形成和生长，与ACSS2抑制肿瘤形成一致。 结肠肿瘤是在独特的代谢环境中发展起来的，在这种环境中，肠道细菌会产生高水平的 单链脂肪酸，包括醋酸盐和丁酸盐。正常的结肠上皮细胞依赖细菌的单链脂肪酸，主要是丁酸，以 他们的能源需求。与ACSS2一样，丁酸代谢酶，包括ACSM3和AADS，是 在结直肠癌中表达下调，低表达与生存不良相关。我们表明，增加ACSM3 Acads基因的表达降低了人CRC细胞系的增殖，而自发缺失Acads的小鼠 更容易患致癌物质诱发的结肠腺瘤。因此，我们的初步数据支持 哪种ACSS2和丁酸代谢酶可以限制肿瘤的发生，特别是在结肠。 我们的总体假设是，ACSS2低表达通过减少组蛋白乙酰化促进结直肠癌 以及它的目标基因的表达，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，它也创造了一种癌症特有的脆弱性， 由此ACSS2低的CRC细胞产生组蛋白乙酰化的乙酰辅酶A的能力受到损害 从头合成脂肪。我们建议通过靶向乙酰来利用这种肿瘤特异性的脆弱性。 辅酶A合成以及依赖ACSS2介导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、人类CRC细胞系和 异种移植以测试ACSS2和AADS是否同时抑制原发结肠肿瘤和转移。2)我们将测试是否 ACSS2通过控制位点特异性的组蛋白乙酰化以及ACSS2是否驱动丁酸代谢基因来限制CRC 表达以增加丁酸的使用和抑制糖酵解。3)我们将检验低ACSS2水平的假设 使结肠肿瘤对依赖ACSS2的染色质模板功能靶向治疗敏感。 本工作将阐明ACSS2在结直肠癌中的一种新的肿瘤抑制功能，确定ACSS2是如何 控制新陈代谢，寻找治疗结直肠癌的新方法。

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.