Acetyl-CoA Metabolism Supports Multistep Pancreatic Tumorigenesis
Acetyl-CoA Metabolism Supports Multistep Pancreatic Tumorigenesis
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DOI：
10.1158/2159-8290.cd-18-0567
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发表时间：
2019-03-01
期刊：
影响因子：
28.2
通讯作者：
Wellen, Kathryn E.
中科院分区：
文献类型：
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作者：
Carrer, Alessandro;Trefely, Sophie;Wellen, Kathryn E.
胰腺导管腺癌(PDA)预后较差，迫切需要新的防治策略。我们先前报道，在癌前病变出现之前，携带Kras突变的胰腺腺泡细胞中组蛋白H4乙酰化水平升高。因为乙酰辅酶A丰度调节全局组蛋白乙酰化，我们假设乙酰辅酶A代谢的改变可能有助于促进肿瘤发生的代谢或表观遗传改变。我们发现，在KRAS突变的腺泡细胞中，乙酰辅酶A的丰度增加，并且它在甲氧戊酸途径中的使用支持腺泡到导管的化生(ADM)。胰腺特异性的乙酰辅酶A产生酶-柠檬酸裂解酶(ACLY)的缺失相应地抑制ADM和肿瘤的形成。在PDA细胞中，生长因子促进AKT-ACLY信号转导和组蛋白乙酰化，同时BET抑制和他汀类药物治疗可抑制细胞增殖和肿瘤生长。因此，KRAS驱动的代谢改变促进了腺泡细胞的可塑性和肿瘤的发展，靶向乙酰辅酶A依赖的过程发挥了抗癌作用。我们确定了代谢酶ACLY在胰腺癌发生中的关键作用，该酶产生乙酰辅酶A。这些数据表明，乙酰辅酶A用于组蛋白乙酰化和甲氧戊酸途径，促进了细胞的可塑性和增殖，这表明有可能针对这些途径。
Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis, and new strategies for prevention and treatment are urgently needed. We previously reported that histone H4 acetylation is elevated in pancreatic acinar cells harboring Kras mutations prior to the appearance of premalignant lesions. Because acetyl-CoA abundance regulates global histone acetylation, we hypothesized that altered acetyl-CoA metabolism might contribute to metabolic or epigenetic alterations that promote tumorigenesis. We found that acetyl-CoA abundance is elevated in KRAS-mutant acinar cells and that its use in the mevalonate pathway supports acinar-to-ductal metaplasia (ADM). Pancreas-specific loss of the acetyl-CoA-producing enzyme ATP-citrate lyase (ACLY) accordingly suppresses ADM and tumor formation. In PDA cells, growth factors promote AKT-ACLY signaling and histone acetylation, and both cell proliferation and tumor growth can be suppressed by concurrent BET inhibition and statin treatment. Thus, KRAS-driven metabolic alterations promote acinar cell plasticity and tumor development, and targeting acetyl-CoA-dependent processes exerts anticancer effects.SIGNIFICANCE : Pancreatic cancer is among the deadliest of human malignancies. We identify a key role for the metabolic enzyme ACLY, which produces acetyl-CoA, in pancreatic carcinogenesis. The data suggest that acetyl-CoA use for histone acetylation and in the mevalonate pathway facilitates cell plasticity and proliferation, suggesting potential to target these pathways.