HDAC5 Loss Enhances Phospholipid-Derived Arachidonic Acid Generation and Confers Sensitivity to cPLA2 Inhibition in Pancreatic Cancer.
HDAC5 Loss Enhances Phospholipid-Derived Arachidonic Acid Generation and Confers Sensitivity to cPLA2 Inhibition in Pancreatic Cancer.
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HDAC5 缺失增强了磷脂衍生的花生四烯酸的生成，并赋予胰腺癌中 cPLA2 抑制的敏感性
DOI：
10.1158/0008-5472.can-21-4362
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发表时间：
2022-12-16
期刊：
影响因子：
11.2
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HDAC5-GATA1-cPLA2-AA信号轴调节胰腺导管腺癌对脂肪限制和cPLA2抑制的敏感性，提示饮食管理是治疗部分胰腺癌患者的可行策略。HDAC5是一种IIa类组蛋白脱乙酰酶成员，在包括胰腺癌在内的多种实体瘤中表达下调，HDAC5缺失与预后不良有关。在这项研究中，对癌症基因组图谱胰腺癌数据集的评估显示，HDAC5的表达与花生四烯酸(AA)代谢呈负相关，花生四烯酸(AA)与炎症反应和癌症进展有关。非靶向代谢组学分析显示，HDAC5基因敲除导致AA及其下游代谢物，如二十烷类化合物和前列腺素的显著增加。HDAC5负调控编码钙依赖的磷脂酶A2(CPLA2)基因的表达，cPLA2是磷脂合成AA的关键酶。机制上，HDAC5通过GATA1的脱乙酰化抑制cPLA2的表达。在体外和体内，癌细胞中的HDAC5基因敲除增强了对cPLA2基因或药物抑制的敏感性。饮食中补充脂肪酸逆转了HDAC5缺陷肿瘤对cPLA2抑制的敏感性。这些数据表明，胰腺癌中HDAC5的缺失导致GATA1的高乙酰化，使cPLA2上调，从而导致AA的过度生产。饮食管理加上cPLA2靶向治疗可以作为治疗HDAC5缺陷的胰腺癌患者的可行策略。HDAC5-GATA1-cPLA2-AA信号轴调节胰腺导管腺癌对脂肪限制和cPLA2抑制的敏感性，提示饮食管理是治疗部分胰腺癌患者的可行策略。
The HDAC5-GATA1-cPLA2-AA signaling axis regulates sensitivity to fat restriction plus cPLA2 inhibition in pancreatic ductal adenocarcinoma, proposing dietary management as a feasible strategy for treating a subset of patients with pancreatic cancer. HDAC5 is a class IIa histone deacetylase member that is downregulated in multiple solid tumors, including pancreatic cancer, and loss of HDAC5 is associated with unfavorable prognosis. In this study, assessment of The Cancer Genome Atlas pancreatic adenocarcinoma dataset revealed that expression of HDAC5 correlates negatively with arachidonic acid (AA) metabolism, which has been implicated in inflammatory responses and cancer progression. Nontargeted metabolomics analysis revealed that HDAC5 knockdown resulted in a significant increase in AA and its downstream metabolites, such as eicosanoids and prostaglandins. HDAC5 negatively regulated the expression of the gene encoding calcium-dependent phospholipase A2 (cPLA2), the key enzyme in the production of AA from phospholipids. Mechanistically, HDAC5 repressed cPLA2 expression via deacetylation of GATA1. HDAC5 knockdown in cancer cells enhanced sensitivity to genetic or pharmacologic inhibition of cPLA2 in vitro and in vivo. Fatty acid supplementation in the diet reversed the sensitivity of HDAC5-deficient tumors to cPLA2 inhibition. These data indicate that HDAC5 loss in pancreatic cancer results in the hyperacetylation of GATA1, enabling the upregulation of cPLA2, which contributes to overproduction of AA. Dietary management plus cPLA2-targeted therapy could serve as a viable strategy for treating HDAC5-deficient pancreatic cancer patients. The HDAC5-GATA1-cPLA2-AA signaling axis regulates sensitivity to fat restriction plus cPLA2 inhibition in pancreatic ductal adenocarcinoma, proposing dietary management as a feasible strategy for treating a subset of patients with pancreatic cancer.