@article{01778b89ec0846cfaeda7e2d7e5611b1,
title = "The abundance of metabolites related to protein methylation correlates with the metastatic capacity of human melanoma xenografts",
abstract = "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 Lys9 and Lys27, 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.",
author = "Xiaolei Shi and Alpaslan Tasdogan and Fang Huang and Zeping Hu and Morrison, {Sean J.} and DeBerardinis, {Ralph J.}",
note = "Funding Information: We thank V. Ramesh and E. Piskounova for help with melanoma xenografts; M. Davies for helpful discussions about melanoma biology; and the UT Southwestern Small Animal Imaging Resource. Funding: R.J.D. was supported by grants from the NIH (1R01 CA157996 06) and the Howard Hughes Medical Institute (Faculty Scholars Program). X.S. was supported by the Howard Hughes Medical Institute International Student Research Fellowship and the Amon G. Carter Foundation. Gifts from Jerry and Emy Lou Baldridge and the Hamon Charitable Foundation also supported this work. A.T. was supported by the Leopoldina Fellowship Program (LPDS 2016-16) from the German National Academy of Sciences Leopoldina. UT Southwestern Small Animal Imaging Resource was supported, in part, by the Harold C. Simmons Comprehensive Cancer Center through a National Cancer Institute Cancer Center Support Grant (1P30 CA142543-01) and the Department of Radiology. S.J.M. is funded by the Cancer Prevention and Research Institute of Texas (P170633). Author contributions: X.S. and R.J.D. conceived the project and designed and interpreted the experiments. S.J.M. provided the PDX models and associated clinical data and participated in the experimental design and data interpretation. X.S. performed most of the experiments with assistance from Z.H., A.T., and F.H. X.S. and R.J.D. wrote the manuscript. Competing interests: R.J.D. is a scientific adviser for Agios Pharmaceuticals. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors. Publisher Copyright: Copyright {\textcopyright} 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.",
year = "2017",
doi = "10.1126/sciadv.aao5268",
language = "English (US)",
volume = "3",
journal = "Science advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "11",
}