Tryptophan restriction blocks MYC-driven tumorigenesis by inhibiting growth pathways and reprograms tumor cells to rely on lipolysis.
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Orbitrap Fusion Lumos
ORGANISM(S): Mus Musculus (ncbitaxon:10090)
SUBMITTER: 
Maralice Conacci-Sorrell
PROVIDER: MSV000089853 | MassIVE | Fri Jul 08 12:20:00 BST 2022
REPOSITORIES: MassIVE
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Project description:Cancer cells vary in their nutritional dependencies, thus characterization of nutrient demand of each tumor type is needed to uncover specific vulnerabilities. We demonstrate that MYC-driven liver tumors rely on increased tryptophan (Trp) uptake to grow. By following 13C-Trp in vivo-labeling, we found that Trp catabolism is reduced while its incorporation into proteins is increased in tumors. Trp deprivation prevents MYC-driven tumors from arising, as well as the growth of xenografted cells while minimally affecting normal cells. Trp starvation causes a reduction in the expression of growth-related and ribosome biogenesis genes while enhancing regulators of lipid metabolism, including PPAR, and enzymes involved in -oxidation and ketosis. Under Trp starvation, surviving cancer cells are reprogramed to utilize lipids; thus, providing a high-fat diet rescued the growth of tumors starved of Trp. We shows that Trp deprivation may be a powerful tool to treat liver tumors if dietary fat intake is low.
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Project description:Tryptophan restriction blocks MYC-driven tumorigenesis and reprograms cancer cells to rely on lipolysis
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Project description:Strain background is BMA64 with RNT1 gene deleted with the TRP marker Media is SD -Trp (synthetic dextrose minimal media missing tryptophan) Cells were grown until midlog and harvested at OD600=0.4; MAS5 (Statistical Algorithm) Scaling:All Probe Sets Target Signal 500;Normalization:All Probe Sets; Alpha1=0.04; Alpha2=0.06; Tau=0.015,Strain background is BMA64 with plasmid expressing TRP marker Media is SD -Trp (synthetic dextrose minimal media missing tryptophan) Cells were grown until midlog and harvested at OD600=0.4,; MAS5 (Statistical Algorithm) Scaling:All Probe Sets Target Signal 500;Normalization:All Probe Sets; Alpha1=0.04; Alpha2=0.06; Tau=0.015
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Project description:In the experimental autoimmune encephalomyelitis (EAE) model we found that omission of the essential amino acid tryptophan (trp) abrogates central nervous system (CNS) autoimmunity. Impaired encephalitogenic T responses were accompanied by an inflammatory response in the colonic mucosa, as well as a profound shift in the gut microbiota. Here, we performed transcriptional profiling of colon tissue by RNA-sequencing 14 days after disease induction in mice that received a trp-free diet or a matched control group to identify key networks that drive this immunosuppressive effect.
2019-11-01 | GSE127190 | GEO
Project description:Strain background is BMA64 with RNT1 gene deleted with the TRP marker Media is SD -Trp (synthetic dextrose minimal media missing tryptophan) Cells were grown until midlog and harvested at OD600=0.4; MAS5 (Statistical Algorithm) Scaling:All Probe Sets Target Signal 500;Normalization:All Probe Sets; Alpha1=0.04; Alpha2=0.06; Tau=0.015 Strain background is BMA64 with plasmid expressing TRP marker Media is SD -Trp (synthetic dextrose minimal media missing tryptophan) Cells were grown until midlog and harvested at OD600=0.4 ; MAS5 (Statistical Algorithm) Scaling:All Probe Sets Target Signal 500;Normalization:All Probe Sets; Alpha1=0.04; Alpha2=0.06; Tau=0.015 Keywords: repeat sample
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Project description:Hepatocellular carcinoma (HCC) represents the third leading cause of cancer-related death worldwide and has been increasing in recent years in developed nations1,2. The MYC oncogene or its paralogs are frequently amplified or overexpressed in particularly aggressive subtypes of cancer associated with stem cell-like features and worse clinical outcomes3,4, including in liver cancer5. Unfortunately, selective inhibitors that target MYC or its transcriptional program are not yet clinically available for therapy of HCC. Here, we identified methionine metabolism as a selective vulnerability for MYC but not RAS-driven liver cancers. MYC-driven liver cancer cells are methionine dependent and S-adenosylmethionine (SAM), the predominant methyl donor, partially rescues methionine depletion. A low methionine diet, or the methylation inhibitor 5-azacytidine limited MYC-driven tumor formation, but RAS-driven liver cancer was resistant to a low methionine diet. Metabolic tracing of methionine catabolism in MYC high cells identified increased m5C methylation of genomic DNA or ribosomal RNA. We identified NOP2, an rRNA m5C-methyltransferase as a MYC target gene. Knockdown of NOP2 selectively inhibited MYC liver cancer cell proliferation and in vivo tumorigenesis. Thus, methionine catabolism is critical for MYC-driven liver tumorigenesis and NOP2 may serve as a new therapeutic target in liver cancer.
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Project description:Aryl hydrocarbon receptor (AHR) activation by tryptophan (Trp) catabolites enhances tumor malignancy and suppresses anti-tumor immunity. Hitherto, indoleamine-2,3-dioxygenase 1 (IDO1) or tryptophan- 2, 3-dioxygenase (TDO2) are recognized as the main Trp-catabolizing enzymes (TCEs) responsible for the generation of AHR agonists. Here, the ability of the aromatic L-amino acid oxidase, interleukin 4 induced 1 (IL4I1), to activate the AHR was investigated using IL4I1 knockout CAS-1 glioblastoma cells.
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Project description:Efforts to therapeutically target EZH2 have generally focused on inhibition of its methyltransferase activity, although it remains less clear whether this is the central mechanism whereby EZH2 promotes cancer. We demonstrate that EZH2 directly interacts with both MYC family oncoproteins, MYC and MYCN, and promotes their stabilization in a methyltransferase-independent manner. By competing against the SCFFBW7 ubiquitin ligase to bind MYC and MYCN, EZH2 counteracted FBW7-mediated MYC(N) polyubiquitination and proteasomal degradation. Depletion, but not enzymatic inhibition, of EZH2 induced robust MYC(N) degradation and inhibited tumor cell growth in MYC(N) driven neuroblastoma and small cell lung cancer. These findings unveil the MYC family proteins as global EZH2 oncogenic effectors and EZH2 pharmacologic degraders as potential MYC(N) targeted cancer therapeutics, pointing out that MYC(N) driven cancers may develop inherent resistance to the canonical EZH2 enzymatic inhibitors currently in clinical development.
2022-02-17 | PXD029652 | Pride
Project description:DNA microarray analysis of gene expression in response to physiological and genetic changes that affect tryptophan metabolism in Escherichia coli. We investigated the global changes in mRNA abundance in Escherichia coli elicited by various perturbations of tryptophan metabolism. To do so we printed DNA microarrays containing 95% of all annotated E. coli ORFs. We determined the expression profile that is predominantly dictated by the activity of the tryptophan repressor. Only three operons, trp, mtr, and aroH, exhibited appreciable expression changes consistent with this profile. The quantitative changes we observed in mRNA levels for the five genes of the trp operon were consistent within a factor of 2, with expectations based on established Trp protein levels. Several operons known to be regulated by the TyrR protein, aroF-tyrA, aroL, aroP, and aroG, were down-regulated on addition of tryptophan. TyrR can be activated by any one of the three aromatic amino acids. Only one operon, tnaAB, was significantly activated by the presence of tryptophan in the medium. We uncovered a plethora of likely indirect effects of changes in tryptophan metabolism on intracellular mRNA pools, most prominent of which was the sensitivity of arginine biosynthetic operons to tryptophan starvation. This study is detailed in Khodursky AB et al.(2000) Proc Natl Acad Sci U S A 97:12170-5 Keywords: other
2001-07-30 | GSE7 | GEO
Project description:We report a comparison of the genome-wide binding patterns of MYC and WDR5, and the effects of a mutation in MYC (WBM) that disrupt the MYC-WDR5 interaction. The experimental design included two distinct experimental strategies. For comparison of genome-wide binding patters of wild-type (WT) and WDR5 binding-deficient (WBM) MYC, HEK293 cells were engineered by retroviral transduction to express either FLAG-tagged WT-MYC, FLAG-tagged WBM-MYC, or an empty vector control ("vec") ChIP was performed on all samples using the anti-FLAG antibody, and co-precipitating DNAs subject to next-generation sequencing. Samples "2514-WPT-1_1", "2514-WPT-5_1" and "2514-WPT-13_1" are three independent biological replicates of ChIPs performed on the "vec" control cells (i.e., those not expressing any exogenous MYC). Samples "2514-WPT-2_1", "2514-WPT-6_1" and "2514-WPT-10_1" are three independent biological replicates of ChIPs performed on the WT-MYC expressing cells. "2514-WPT-3_1", "2514-WPT-7_1" and "2514-WPT-11_1" are three independent biological replicates of ChIPs performed on the WBM-MYC expressing cells. For comparison of these binding patterns with those of WDR5, we performed ChIP in HEK293 cells with either an antibody against WDR5, or with IgG (negative control). Samples "2514-WPT-23_1", "2514-WPT-25_1", and "2514-WPT-27_1" are independent biological replicates of ChIPs performed with the anti-WDR5 antibody. Samples "2514-WPT-24_1", "2514-WPT-26_1", and "2514-WPT-28_1" are independent biological replicates of ChIPs performed with the negative IgG control.
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