Menin regulates the serine biosynthetic pathway in Ewing sarcoma
Developmental transcription programs are epigenetically controlled by multi-protein complexes, such as the menin- and MLL-that contains trithorax (TrxG) complexes, which promote gene transcription by depositing the H3K4me3 activating mark at target gene promoters. We lately reported that in Ewing sarcoma, MLL1 (lysine methyltransferase 2A, KMT2A) and menin are overexpressed and performance as oncogenes. Small molecule inhibition from the menin-MLL interaction results in lack of menin and MLL1 protein expression, and also to inhibition of growth and tumorigenicity. Here, we’ve investigated the mechanistic foundation of menin-MLL-mediated oncogenic activity in Ewing sarcoma. Bromouridine sequencing (Bru-seq) was performed to recognize alterations in nascent gene transcription in Ewing sarcoma cells, following contact with the menin-MLL interaction inhibitor MI-503. Menin-MLL inhibition led to early and prevalent reprogramming of metabolic processes. Particularly, the serine biosynthetic path (SSP) was the path most considerably impacted by MI-503 treatment. Baseline expression of SSP genes and proteins (PHGDH, PSAT1, and PSPH), and metabolic flux with the SSP were confirmed to become full of Ewing sarcoma. Additionally, inhibition of PHGDH led to reduced cell proliferation, viability, and tumor development in vivo, revealing a vital dependency of Ewing sarcoma around the SSP. Lack of function studies validated a mechanistic outcomes of menin and also the SSP. Particularly, inhibition of menin led to reduced expression of SSP genes, reduced H3K4me3 enrichment in the PHGDH promoter, and finish abrogation of de novo serine and glycine biosynthesis, as shown by MI-503 metabolic tracing studies with 13 C-labeled glucose. These data show the SSP is extremely active in Ewing sarcoma which its oncogenic activation is maintained, a minimum of partly, by menin-dependent epigenetic mechanisms involving trithorax complexes. Copyright © 2018 Pathological Society of effective Britain and Ireland. Printed by John Wiley & Sons, Limited.