Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Sci Adv. 2017 Nov 1;3(11):eaao5268. doi: 10.1126/sciadv.aao5268. eCollection 2017 Nov.
Metabolic reprogramming is a major factor in transformation, and particular metabolic phenotypes correlate with oncogenotype, tumor progression, and metastasis. By profiling metabolites in 17 patient-derived xenograft melanoma models, we identified durable metabolomic signatures that correlate with biological features of the tumors. BRAF mutant tumors had metabolomic and metabolic flux features of enhanced glycolysis compared to BRAF wild-type tumors. Tumors that metastasized efficiently from their primary sites had elevated levels of metabolites related to protein methylation, including trimethyllysine (TML). TML levels correlated with histone H3 trimethylation at Lys and Lys, and methylation at these sites was also enhanced in efficiently metastasizing tumors. Erasing either of these marks by genetically or pharmacologically silencing the histone methyltransferase SETDB1 or EZH2 had no effect on primary tumor growth but reduced cellular invasiveness and metastatic spread. Thus, metabolite profiling can uncover targetable epigenetic requirements for the metastasis of human melanoma cells.
代谢重编程是转化的一个主要因素，特定的代谢表型与致癌基因型、肿瘤进展和转移相关。通过对 17 种患者来源的异种移植黑色素瘤模型中的代谢物进行分析，我们确定了与肿瘤生物学特征相关的持久代谢组学特征。与 BRAF 野生型肿瘤相比，BRAF 突变型肿瘤具有增强的糖酵解代谢组学和代谢通量特征。从原发部位高效转移的肿瘤中，与蛋白质甲基化相关的代谢物水平升高，包括三甲基赖氨酸（TML）。TML 水平与组蛋白 H3 在赖氨酸和赖氨酸上的三甲基化相关，并且在高效转移的肿瘤中这些位点的甲基化也增强。通过遗传或药理学沉默组蛋白甲基转移酶 SETDB1 或 EZH2 来消除这些标记中的任何一个，对原发性肿瘤的生长都没有影响，但降低了细胞侵袭性和转移扩散。因此，代谢产物谱分析可以揭示针对人类黑色素瘤细胞转移的可靶向表观遗传需求。
