Lactate dehydrogenase A silencing in IDH mutant gliomas
Lactate dehydrogenase A silencing in IDH mutant gliomas
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DOI：
10.1093/neuonc/not243
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发表时间：
2014-05-01
期刊：
影响因子：
15.9
通讯作者：
Cairncross, J. Gregory
中科院分区：
文献类型：
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作者：
Chesnelong, Charles;Chaumeil, Myriam M.;Cairncross, J. Gregory
异柠檬酸脱氢酶1和2基因（IDH 1/2）的突变最初被认为通过促进瓦尔堡效应来增强癌细胞存活和增殖。然而，最近的实验数据表明，IDH突变细胞产生的2-羟基戊二酸促进缺氧诱导因子（HIF）1的降解，并通过这样做，可能有意想不到的代谢effects.We使用人胶质瘤组织和衍生的脑肿瘤干细胞（BTSC）研究HIF 1靶基因在IDH突变（（mt））和IDH野生型（（wt））肿瘤的表达。随后，我们聚焦于主要的糖酵解酶乳酸脱氢酶A（LDHA），使用标准的分子方法和基于焦磷酸测序的DNA甲基化分析来确定LDHA表达在人脑胶质瘤中调节的机制，我们发现HIF 1应答基因，包括许多糖酵解必需的基因（SLC 2A 1，PDK 1，LDHA，SLC 16 A3），在IDHmt胶质瘤和/或衍生的BTSC中表达不足。然后，我们证明了LDHA在IDHmt衍生的BTSC中沉默，包括那些不保留突变体IDH 1等位基因（mIDH（wt））的BTSC、匹配的BTSC异种移植物和亲本胶质瘤组织。LDHA的沉默与LDHA启动子的甲基化增加相关，因为在永生化的人星形胶质细胞中突变IDH 1的异位表达也是如此。此外，在癌症基因组图谱的搜索中，我们发现LDHA在IDHmt胶质母细胞瘤中低表达和高甲基化。据我们所知，这是LDHA在癌症中下调的第一个证明。虽然出乎意料的发现，LDHA的沉默和其他几个糖酵解必需基因的下调提出了有趣的可能性，IDHmt胶质瘤具有有限的糖酵解能力，这可能有助于其缓慢的生长和更好的预后。
Mutations of the isocitrate dehydrogenase 1 and 2 gene (IDH1/2) were initially thought to enhance cancer cell survival and proliferation by promoting the Warburg effect. However, recent experimental data have shown that production of 2-hydroxyglutarate by IDH mutant cells promotes hypoxia-inducible factor (HIF)1 degradation and, by doing so, may have unexpected metabolic effects.We used human glioma tissues and derived brain tumor stem cells (BTSCs) to study the expression of HIF1 target genes in IDH mutant ((mt)) and IDH wild-type ((wt)) tumors. Focusing thereafter on the major glycolytic enzyme, lactate dehydrogenase A (LDHA), we used standard molecular methods and pyrosequencing-based DNA methylation analysis to identify mechanisms by which LDHA expression was regulated in human gliomas.We found that HIF1-responsive genes, including many essential for glycolysis (SLC2A1, PDK1, LDHA, SLC16A3), were underexpressed in IDHmt gliomas and/or derived BTSCs. We then demonstrated that LDHA was silenced in IDHmt derived BTSCs, including those that did not retain the mutant IDH1 allele (mIDH(wt)), matched BTSC xenografts, and parental glioma tissues. Silencing of LDHA was associated with increased methylation of the LDHA promoter, as was ectopic expression of mutant IDH1 in immortalized human astrocytes. Furthermore, in a search of The Cancer Genome Atlas, we found low expression and high methylation of LDHA in IDHmt glioblastomas.To our knowledge, this is the first demonstration of downregulation of LDHA in cancer. Although unexpected findings, silencing of LDHA and downregulation of several other glycolysis essential genes raise the intriguing possibility that IDHmt gliomas have limited glycolytic capacity, which may contribute to their slow growth and better prognosis.