Jung Jinkyu, Kim Leo Jy, Wang Xiuxing, Wu Qiulian, Sanvoranart Tanwarat, Hubert Christopher G, Prager Briana C, Wallace Lisa C, Jin Xun, Mack Stephen C, Rich Jeremy N
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine.
JCI Insight. 2017 May 18;2(10). doi: 10.1172/jci.insight.90019.
Metabolic dysregulation promotes cancer growth through not only energy production, but also epigenetic reprogramming. Here, we report that a critical node in methyl donor metabolism, nicotinamide N-methyltransferase (NNMT), ranked among the most consistently overexpressed metabolism genes in glioblastoma relative to normal brain. NNMT was preferentially expressed by mesenchymal glioblastoma stem cells (GSCs). NNMT depletes S-adenosyl methionine (SAM), a methyl donor generated from methionine. GSCs contained lower levels of methionine, SAM, and nicotinamide, but they contained higher levels of oxidized nicotinamide adenine dinucleotide (NAD+) than differentiated tumor cells. In concordance with the poor prognosis associated with DNA hypomethylation in glioblastoma, depletion of methionine, a key upstream methyl group donor, shifted tumors toward a mesenchymal phenotype and accelerated tumor growth. Targeting NNMT expression reduced cellular proliferation, self-renewal, and in vivo tumor growth of mesenchymal GSCs. Supporting a mechanistic link between NNMT and DNA methylation, targeting NNMT reduced methyl donor availability, methionine levels, and unmethylated cytosine, with increased levels of DNA methyltransferases, DNMT1 and DNMT3A. Supporting the clinical significance of these findings, NNMT portended poor prognosis for glioblastoma patients. Collectively, our findings support NNMT as a GSC-specific therapeutic target in glioblastoma by disrupting oncogenic DNA hypomethylation.
代谢失调不仅通过能量产生促进癌症生长，还通过表观遗传重编程来实现。在此，我们报告甲基供体代谢中的一个关键节点，烟酰胺N-甲基转移酶（NNMT），在胶质母细胞瘤中相对于正常脑组织而言，是最持续高表达的代谢基因之一。NNMT优先由间充质胶质母细胞瘤干细胞（GSCs）表达。NNMT会消耗S-腺苷甲硫氨酸（SAM），一种由甲硫氨酸生成的甲基供体。GSCs中甲硫氨酸、SAM和烟酰胺的水平较低，但与分化的肿瘤细胞相比，它们含有更高水平的氧化型烟酰胺腺嘌呤二核苷酸（NAD+）。与胶质母细胞瘤中DNA低甲基化相关的不良预后一致，关键上游甲基供体甲硫氨酸的消耗使肿瘤向间充质表型转变并加速肿瘤生长。靶向NNMT表达可降低间充质GSCs的细胞增殖、自我更新和体内肿瘤生长。靶向NNMT可降低甲基供体可用性、甲硫氨酸水平和未甲基化的胞嘧啶，同时增加DNA甲基转移酶DNMT1和DNMT3A的水平，这支持了NNMT与DNA甲基化之间的机制联系。这些发现的临床意义在于，NNMT预示着胶质母细胞瘤患者的预后不良。总体而言，我们的研究结果支持将NNMT作为胶质母细胞瘤中GSC特异性治疗靶点，通过破坏致癌性DNA低甲基化来实现。
