Human Gene Set: BEAUCHAMP_MISS_54_MYRISTOYLATION_INHIBITION_SENSITIVE_SIGNATURE


Standard name BEAUCHAMP_MISS_54_MYRISTOYLATION_INHIBITION_SENSITIVE_SIGNATURE
Systematic name M49138
Brief description Genes upregulated in cancer cell lines sensitive to N-myristoyltransferase (NMT) inhibition
Full description or abstract This gene set consists of 54 genes (MISS-54) whose expression correlates with cancer cell sensitivity to N-myristoyltransferase inhibition (NMTI). Transcriptomic analysis of 1200 NMT inhibitor (NMTI)-treated cancer cell lines revealed that NMTI sensitivity relates not only to NMT2 loss or NMT1 dependency, but also correlates with a myristoylation inhibition sensitivity signature comprising 54 genes (MISS-54) enriched in hematologic cancers as well as testis, brain, lung, ovary, and colon cancers. Because non-myristoylated proteins are degraded by a glycine-specific N-degron, differential proteomics revealed the major impact of abrogating NMT1 genetically using CRISPR/Cas9 in cancer cells was surprisingly to reduce mitochondrial respiratory complex I proteins rather than cell signaling proteins, some of which were also reduced, albeit to a lesser extent. Cancer cell treatments with the first-in-class NMTI PCLX-001 (zelenirstat), which is undergoing human phase 1/2a trials in advanced lymphoma and solid tumors, recapitulated these effects. The most downregulated myristoylated mitochondrial protein was NDUFAF4, a complex I assembly factor. Knockout of NDUFAF4 or in vitro cell treatment with zelenirstat resulted in loss of complex I, oxidative phosphorylation and respiration, which impacted metabolomes.
Collection C2: Curated
      CGP: Chemical and Genetic Perturbations
Source publication Pubmed 38715059   Authors: Beauchamp E,Gamma JM,Cromwell CR,Moussa EW,Pain R,Kostiuk MA,Acevedo-Morantes C,Iyer A,Yap M,Vincent KM,Postovit LM,Julien O,Hubbard BP,Mackey JR,Berthiaume LG
Exact source Table S4 (12967_2024_5150_MOESM2_ESM)
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External links https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-05150-6
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Source species Homo sapiens
Contributed by Anthony Castanza (MSigDB Team)
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identifier namespace		 HUMAN_GENE_SYMBOL
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GTEx compendium
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Global Cancer Map (Broad Institute)
NCI-60 cell lines (National Cancer Institute)
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Version history 2025.1.Hs: First Introduced.

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