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Menin regulates the serine biosynthetic pathway in Ewing sarcoma

dc.contributor.authorSvoboda, Laurie K
dc.contributor.authorTeh, Selina Shiqing K
dc.contributor.authorSud, Sudha
dc.contributor.authorKerk, Samuel
dc.contributor.authorZebolsky, Aaron
dc.contributor.authorTreichel, Sydney
dc.contributor.authorThomas, Dafydd
dc.contributor.authorHalbrook, Christopher J
dc.contributor.authorLee, Ho‐joon
dc.contributor.authorKremer, Daniel
dc.contributor.authorZhang, Li
dc.contributor.authorKlossowski, Szymon
dc.contributor.authorBankhead, Armand R
dc.contributor.authorMagnuson, Brian
dc.contributor.authorLjungman, Mats
dc.contributor.authorCierpicki, Tomasz
dc.contributor.authorGrembecka, Jolanta
dc.contributor.authorLyssiotis, Costas A
dc.contributor.authorLawlor, Elizabeth R
dc.date.accessioned2018-07-13T15:48:40Z
dc.date.available2019-09-04T20:15:39Zen
dc.date.issued2018-07
dc.identifier.citationSvoboda, Laurie K; Teh, Selina Shiqing K; Sud, Sudha; Kerk, Samuel; Zebolsky, Aaron; Treichel, Sydney; Thomas, Dafydd; Halbrook, Christopher J; Lee, Ho‐joon ; Kremer, Daniel; Zhang, Li; Klossowski, Szymon; Bankhead, Armand R; Magnuson, Brian; Ljungman, Mats; Cierpicki, Tomasz; Grembecka, Jolanta; Lyssiotis, Costas A; Lawlor, Elizabeth R (2018). "Menin regulates the serine biosynthetic pathway in Ewing sarcoma." The Journal of Pathology 245(3): 324-336.
dc.identifier.issn0022-3417
dc.identifier.issn1096-9896
dc.identifier.urihttps://hdl.handle.net/2027.42/144706
dc.description.abstractDevelopmental transcription programs are epigenetically regulated by multiâ protein complexes, including the meninâ and MLLâ 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 meninâ 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 meninâ MLLâ mediated oncogenic activity in Ewing sarcoma. Bromouridine sequencing (Bruâ seq) was performed to identify changes in nascent gene transcription in Ewing sarcoma cells, following exposure to the meninâ MLL interaction inhibitor MIâ 503. Meninâ 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 MIâ 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 13Câ 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 meninâ dependent epigenetic mechanisms involving trithorax complexes. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
dc.publisherJohn Wiley & Sons, Ltd
dc.subject.othercancer metabolism
dc.subject.otherepigenetic
dc.subject.otherEWSâ FLI1
dc.subject.otherEwing sarcoma
dc.subject.otherPHGDH
dc.titleMenin regulates the serine biosynthetic pathway in Ewing sarcoma
dc.typeArticleen_US
dc.rights.robotsIndexNoFollow
dc.subject.hlbsecondlevelPathology
dc.subject.hlbtoplevelHealth Sciences
dc.description.peerreviewedPeer Reviewed
dc.description.bitstreamurlhttps://deepblue.lib.umich.edu/bitstream/2027.42/144706/1/path5085_am.pdf
dc.description.bitstreamurlhttps://deepblue.lib.umich.edu/bitstream/2027.42/144706/2/path5085.pdf
dc.identifier.doi10.1002/path.5085
dc.identifier.sourceThe Journal of Pathology
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dc.owningcollnameInterdisciplinary and Peer-Reviewed


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