期刊
JOURNAL OF PATHOLOGY
卷 245, 期 3, 页码 324-336出版社
WILEY
DOI: 10.1002/path.5085
关键词
cancer metabolism; PHGDH; epigenetic; EWS-FLI1; Ewing sarcoma
资金
- SARC Sarcoma SPORE [1U54-CA168512]
- Hyundai Hope on Wheels
- Russell G Adderley Endowment (ERL)
- National Institutes of Health [1R01-CA160467, 1R01-CA-200660]
- Leukemia and Lymphoma Society Scholar grant [1215-14]
- Dale F Frey Award for Breakthrough Scientists from the Damon Runyon Cancer Research Foundation [DFS-09-14]
- Junior Scholar Award from The V Foundation for Cancer Research [V2016-009]
- Kimmel Scholar Award from the Sidney Kimmel Foundation for Cancer Research [SKF-16-005]
- AACR NextGen Grant for Transformative Cancer Research [17-20-01-LYSS]
- NIH [DK097153]
- UMCCC Core Grant [P30 CA046592]
- Hartwell Foundation Postdoctoral Fellowship
- Charles Woodson Research Fund
- Alex's Lemonade Stand Pediatric Oncology Student Training Program
- Cancer Biology training grant [T32CA009676]
- Michigan Institute for Translational AMP
- Clinical Research Postdoctoral Translational Scholars Program [UL1TR000433]
- NATIONAL CANCER INSTITUTE [R01CA160467, T32CA009676, R01CA200660, P30CA046592, R01CA218116, U54CA168512] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR002240, UL1TR000433] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [U24DK097153] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R25GM086262] Funding Source: NIH RePORTER
Developmental transcription programs are epigenetically regulated by multi-protein complexes, including the menin- and MLL-containing trithorax (TrxG) complexes, which promote gene transcription by depositing the H3K4me3 activating mark at target gene promoters. We recently reported that in Ewing sarcoma, MLL1 (lysine methyltransferase 2A, KMT2A) and menin are overexpressed and function as oncogenes. Small molecule inhibition of the menin-MLL interaction leads to loss of menin and MLL1 protein expression, and to inhibition of growth and tumorigenicity. Here, we have investigated the mechanistic basis of menin-MLL-mediated oncogenic activity in Ewing sarcoma. Bromouridine sequencing (Bru-seq) was performed to identify changes in nascent gene transcription in Ewing sarcoma cells, following exposure to the menin-MLL interaction inhibitor MI-503. Menin-MLL inhibition resulted in early and widespread reprogramming of metabolic processes. In particular, the serine biosynthetic pathway (SSP) was the pathway most significantly affected by MI-503 treatment. Baseline expression of SSP genes and proteins (PHGDH, PSAT1, and PSPH), and metabolic flux through the SSP were confirmed to be high in Ewing sarcoma. In addition, inhibition of PHGDH resulted in reduced cell proliferation, viability, and tumor growth in vivo, revealing a key dependency of Ewing sarcoma on the SSP. Loss of function studies validated a mechanistic link between menin and the SSP. Specifically, inhibition of menin resulted in diminished expression of SSP genes, reduced H3K4me3 enrichment at the PHGDH promoter, and complete abrogation of de novo serine and glycine biosynthesis, as demonstrated by metabolic tracing studies with C-13-labeled glucose. These data demonstrate that the SSP is highly active in Ewing sarcoma and that its oncogenic activation is maintained, at least in part, by menin-dependent epigenetic mechanisms involving trithorax complexes. Copyright (C) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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