HIF-1-Mediated Suppression of Acyl-CoA Dehydrogenases and Fatty Acid Oxidation Is Critical for Cancer Progression
HIF-1-Mediated Suppression of Acyl-CoA Dehydrogenases and Fatty Acid Oxidation Is Critical for Cancer Progression
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HIF-1 介导的酰基辅酶 A 脱氢酶和脂肪酸氧化抑制对于癌症进展至关重要
DOI：
10.1016/j.celrep.2014.08.028
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发表时间：
2014-09-25
期刊：
影响因子：
8.8
通讯作者：
Zhang, Huafeng
中科院分区：
文献类型：
--
作者：
Huang, De;Li, Tingting;Zhang, Huafeng
缺氧诱导因子1（HIF-1）介导的代谢开关，阻断癌细胞中丙酮酸转化为乙酰辅酶A。在这里，我们报告说，HIF-1 α也抑制脂肪酸β-氧化（FAO），乙酰辅酶A的另一个主要来源。我们确定了PGC-1 β介导的途径，通过该途径HIF-1抑制中链和长链酰基辅酶A脱氢酶（MCAD和LCAD），导致活性氧水平降低和增殖增强。令人惊讶的是，我们进一步发现，阻断LCAD而不是MCAD，钝化了PTEN表达，并显着影响体内肿瘤生长。对158例肝癌样本的分析表明，LCAD表达降低可预测患者死亡率。总之，我们已经确定了一个以前不受重视的机制，HIF-1抑制FAO促进癌症进展。
Hypoxia-inducible factor 1 (HIF-1) mediates a metabolic switch that blocks the conversion of pyruvate to acetyl-CoA in cancer cells. Here, we report that HIF-1 alpha also inhibits fatty acid beta-oxidation (FAO), another major source of acetyl-CoA. We identified a PGC-1 beta-mediated pathway by which HIF-1 inhibits the medium- and long-chain acyl-CoA dehydrogenases (MCAD and LCAD), resulting in decreased reactive oxygen species levels and enhanced proliferation. Surprisingly, we further uncovered that blocking LCAD, but not MCAD, blunts PTEN expression and dramatically affects tumor growth in vivo. Analysis of 158 liver cancer samples showed that decreased LCAD expression predicts patient mortality. Altogether, we have identified a previously unappreciated mechanism by which HIF-1 suppresses FAO to facilitate cancer progression.