HDAC inhibitors elicit metabolic reprogramming by targeting super-enhancers in glioblastoma models
HDAC inhibitors elicit metabolic reprogramming by targeting super-enhancers in glioblastoma models
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DOI：
10.1172/jci129049
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发表时间：
2020-07-01
影响因子：
15.9
通讯作者：
Siegelin, Markus D.
中科院分区：
文献类型：
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作者：
Trang Thi Thu Nguyen;Zhang, Yiru;Siegelin, Markus D.
瓦尔堡效应是一种与肿瘤相关的现象，有可能成为治疗靶点。在这里，我们发现胶质母细胞瘤（GBM）培养物和患者的肿瘤在与瓦尔堡效应相关的几个基因中含有超级增强子。通过在GBM模型中进行转录组分析，然后进行ChIP-Seq结合综合代谢物分析，我们发现FDA批准的全局（帕比司他、伏立诺他）和选择性（罗米地辛）组蛋白脱乙酰酶（HDAC）抑制剂引起代谢重编程，同时破坏几种瓦尔堡效应相关的超级增强子。细胞外通量和碳示踪分析表明，HDAC抑制剂钝化糖酵解的c-Myc依赖性的方式和降低ATP水平。这导致参与由升高的脂肪酸氧化（FAO）驱动的氧化磷酸化（OXPHOS），使得GBM细胞依赖于这些途径。从机制上讲，HDAC 1/-2的干扰引起c-Myc蛋白水平的抑制，并伴随着氧化代谢的2种转录驱动因子PGC 1 α和PPARD的增加，这表明了相反的关系。拯救和ChIP实验表明，c-Myc与PGC 1 α和PPARD的启动子区结合，以抵消HDAC 1/-2抑制驱动的上调。最后，我们证明了在没有毒性的情况下，HDAC和FAO抑制剂的组合治疗比单一治疗更有效地延长了体内患者来源的异种移植模型系统中的动物存活。
The Warburg effect is a tumor-related phenomenon that could potentially be targeted therapeutically. Here, we showed that glioblastoma (GBM) cultures and patients' tumors harbored super-enhancers in several genes related to the Warburg effect. By conducting a transcriptome analysis followed by ChIP-Seq coupled with a comprehensive metabolite analysis in GBM models, we found that FDA-approved global (panobinostat, vorinostat) and selective (romidepsin) histone deacetylase (HDAC) inhibitors elicited metabolic reprogramming in concert with disruption of several Warburg effect-related super-enhancers. Extracellular flux and carbon-tracing analyses revealed that HDAC inhibitors blunted glycolysis in a c-Myc-dependent manner and lowered ATP levels. This resulted in the engagement of oxidative phosphorylation (OXPHOS) driven by elevated fatty acid oxidation (FAO), rendering GBM cells dependent on these pathways. Mechanistically, interference with HDAC1/-2 elicited a suppression of c-Myc protein levels and a concomitant increase in 2 transcriptional drivers of oxidative metabolism, PGC1 alpha and PPARD, suggesting an inverse relationship. Rescue and ChIP experiments indicated that c-Myc bound to the promoter regions of PGC1 alpha and PPARD to counteract their upregulation driven by HDAC1/-2 inhibition. Finally, we demonstrated that combination treatment with HDAC and FAO inhibitors extended animal survival in patient-derived xenograft model systems in vivo more potently than single treatments in the absence of toxicity.