MetaboLightsapplication/xmlftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS14411/m_MTBLS14411_LC-MS_positive_hilic_v2_maf.tsvftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS14411/i_Investigation.txtftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS14411/s_MTBLS14411.txtftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS14411/a_MTBLS14411_LC-MS_positive_hilic.txtprimaryOK200ftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS14411<p>These metabolites were annotated using the KEGG database (https://www.genome.jp/kegg/pathway.html)&nbsp;, HMDB database(https://hmdb.ca/ metabolites).</p>MetaboLightsPublicLiquid Chromatography MS - positive - hilic<p>&nbsp;Targeted metabolomics analysis was performed using Shimadzu Prominence HPLC system (ExionLC AD) interfaced with a QTRAP 6500+ system (AB SCIEX). The sample injection volume was 5 µl. Metabolites were separated through an iHILIC-(P) Classic HILIC column (100 × 4.6 mm with 3.5 μm particle size, Waters) with column temperature maintained at 40&nbsp;°C. Mobile phases consisted of 20 mM ammonium acetate in 25 mM ammonia water (mobile phase A) and acetonitrile (mobile phase B) and was run at a flow rate of 0.4 ml/min. The gradient was as follows: 0 min, 85% B; 0.1 min, 85% B; 3.5 min, 32% B; 12 min, 2% B; 16.5 min, 2% B; 17 min, 85% B; 26 min, 85% B.&nbsp;</p>LKB1 inactivation elicits a NNMT-mediated methyl sink and confers dependence on PRMT5 in lung cancer.Fudan UniversityWen Micell culturemass spectrometry assay<p>Targeted Metabolomics was performed as previously1. For metabolite extraction, medium was removed by aspiration and metabolism was immediately quenched (without any washing steps) by adding 500 μl −20&nbsp;°C 40:40:20 acetonitrile: methanol: water containing 0.5% formic acid. After about 5~10 s, cell extract was neutralized with 44&nbsp;μl 15% ammonium bicarbonate. The cell extracts were transferred to 1.5 ml tubes and stored at -80&nbsp;°C overnight and further cleared by centrifuging to remove protein at 15,000&nbsp;×&nbsp;g for 10 minutes. The supernatant was used for LC-MS analysis.&nbsp;</p>Homo sapienshttps://www.ebi.ac.uk/metabolights/MTBLS14411Wen Mi. Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University. 21110880013@m.fudan.edu.cn.<p>Data were processed and analyzed using SCIEX OS software and normalized to cell number in each group.</p>Treatment21110880013@m.fudan.edu.cn<p>Aspirate all the culture medium from the dish, add an appropriate amount of PBS for washing, and repeat once or twice to remove the medium as completely as possible. Add 1-2 mL of HPLC-grade 80% (vol/vol) methanol to the dish, then use a cell scraper to collect the methanol-cell mixture and transfer it to a 15 mL centrifuge tube. Keep the tube on ice. Add another 1 mL of HPLC-grade 80% methanol to the dish and combine it with the contents in the centrifuge tube. Transfer the centrifuge tube to a -80°C freezer and incubate overnight.</p>MetabolomicsMetabolomicsPRMT5SenescenceNNMTuntargeted analysisHomo sapiensuntargeted metabolite profilingAB SCIEX QTRAP 6500+SCIEX ExionLC ADcell culture2-(1-hydroxyethyl)-4-methylpentanoic acid-4-O-glucopyranosideexperimental blanklkb1MetabolomicsPRMT5SenescenceNNMTuntargeted analysisHomo sapiensuntargeted metabolite profilingAB SCIEX QTRAP 6500+SCIEX ExionLC ADcell culture2-(1-hydroxyethyl)-4-methylpentanoic acid-4-O-glucopyranosideexperimental blanklkb1<p>The mass spectrometer was run in multiple reactions monitoring (MRM) mode. The ESI source parameters: source temperature of 475 °C, the ion source gas 1 and 2 at 60 psi, the curtain gas at 35 psi, the ion spray voltage at 4850 V or -4500 V for positive or negative modes. </p>dGDPS-AdenosylmethioninamineDL-2-Aminooctanoic acidPhenylacetylglutamineRiboflavinPyrocatechol3,3-Dimethylglutaric acidFolic acidCDPgamma-Aminobutyric acidDeoxyinosine8-Aminooctanoic acidMethyl nicotinateIndole-3-methyl acetateKinetinKetoleucineL-Histidine2-Methylbenzoic acidTramiprosateFlavoneOxoglutaric acidPhenylglyoxylic acidBiotinGlucosamine-1PCitrullineL-ProlineUreaD-Glucuronic acidFlavin mononucleotideN1-Acetylspermidine3-Hydroxyanthranilic acidL-Alanine methyl ester hydrochloride4-HydroxybenzaldehydeN2-AcetylornithineGlucosamineThymidine 5'-triphosphateCinnamic acidMethylglutaric acid1,2,3-TrihydroxybenzeneGlycineL-Pipecolic acidL-AsparagineN6-Acetyl-L-lysineGuanosine monophosphateOleic acidGlutaric acidImidazoleMevalonolactoneGlutathioneAdenylsuccinic acidS-RibosylhomocysteineUridine diphosphate-N-acetylglucosamineMethylcysteine5-HydroxylysineCaffeic acid2-Methylglutaric acidN-AcetylcadaverineProline betaineSalicylamideN-Acetylneuraminic acid4-Pyridoxic acid2-Oxo-4-methylthiobutanoic acidPantothenic acidGlycerol 3-phosphateDiethylphosphateGuanosineRibothymidineN-Acetyl-L-methionineGlyceraldehyde 3-phosphate(s)-Atrolactic acidXanthurenic acidADPShikimic acidAlanylglutamineAcetylglycineShikimate-3-phosphated7-S1PAcetoacetic acidGlyceric acidGlycylvalineArachidoyl-CoAHomoveratric acidAminoadipic acidCyclic AMPDeoxyribose 5-phosphate2-Aminoisobutyric acid5-Methoxytryptamine2-Indolecarboxylic acidtrans-trans-Muconic acidOxidized glutathioneMethylguanidineOxalacetic acidUridineoctose 1,8-bisphosphateL-Homocysteic acidOrnithine3-Hydroxybenzoic acidD-GlucoseIndoleEquol3-Sulfinoalanine3-Methylphenylacetic acidIsocitric aciddTDPL-CarnitineMalonyl-CoAAdenosine triphosphateThiamineEthanolamineAdenosineAdenosine monophosphateN-Acetyl-L-glutamic acidUric acidPhosphoribosyl pyrophosphateAcetylphosphateGuanidoacetic acidNADHomogentisic acidFumaric acidL-Tyrosine5-Phenylvaleric acidD-Erythrose 4-phosphateArgininosuccinic acidHomo-L-arginineBis(3',5')-cyclic diguanylic acid3-Hydroxybutyric acidBenzoic acidPhenylpyruvic acidMelatoninAscorbic acidL-PhenylalanineSucrosedCDP5-Methylcytosine2'-Deoxyguanosine 5'-monophosphateMethylsuccinic acidThioguanineGlycylprolineO-AcetylserineSedoheptulose 1,7-bisphosphate2-Pyrocatechuic acidSpermidineUridine diphosphate glucoseSphingosineN-Acetyl-L-tyrosineFolinic acid2-Isopropylmalic acid2-Ketobutyric acidNicotinamide ribosideUrocanic acid3-Indolebutyric acidRibitolL-CystathionineAICARHydroxyoctanoic acidFarnesyl pyrophosphate3-Methoxybenzenepropanoic acid5-MethylcytidineGuanineAminomalonic acid5'-Methylthioadenosine4-Nitrophenol1-MethylnicotinamideNADH2-HydroxypyridineNADP2-Keto-L-gluconateCreatinineCiticolineXanthosinePyridoxinePimelic acidDesaminotyrosineUridine 5'-monophosphateGlycylleucineCitric acid6-Phosphogluconic acidGuanosine triphosphateCyclamic acidN-AcetylleucineN-a-Acetyl-L-arginineHydroxyisocaproic acidGalactose 1-phosphateSuccinyl-CoABilirubinNicotinamide ribotide5-Methoxytryptophan5-Methyldeoxycytidine5-Methyltetrahydrofolic acidItaconic acidBetaineGlucose 6-phosphateL-Alanine4-Aminohippuric acidStachyoseStearic acidCDP-ethanolamine4-Acetamidobutanoic acidXanthylic acidDeoxyuridine triphosphate2-Hydroxycaproic acid6-Hydroxynicotinic acid2-Hydroxy-3-methylbutyric acidCytidineDehydroascorbic acidSymmetric dimethylarginine2-PhenylpropionateL-LysineTrimethylamine N-oxideMALEAMIC ACID3-Hydroxyisovaleric acidHydroxypropionic acid(3HP)Dimethylbenzimidazole1-MethylhistidineGlyoxylic acidUridine 5'-diphosphatecis-Aconitic acidFluorouracil3,5-Diiodothyronine2',4',6'-TrihydroxyacetophenoneGuanosine 3',5'-bis(diphosphate)ThymineN-Acetylasparagine4,4,5,5-tetradeuterolysine4,5-Dihydroorotic acid1-Methyladenosine6-O-phosphonato-D-glucono-1,5-lactone(2-)3,5-Diiodo-L-tyrosine3-Amino-4-hydroxybenzoic acidSarcosinedUMPTaurineD-FructoseMonomethyl glutaric acidAllantoinHydrocinnamic acidGlucaric acid5-Thymidylic acidO-PhosphoethanolamineFructose 1,6-bisphosphateL-HomoserineDihydrofolic acidThiamine pyrophosphateD-Ribose 5-phosphate2-HydroxyethanesulfonateL-ThreonineGuanosine diphosphatep-SynephrineKynurenic acidPropionyl-CoAbeta-AlanineMyristoleic acid4-AminophenolL-LeucineTrigonellinePyridoxalThiamine monophosphateGlycerolalpha-Ketoisovaleric acidInosine triphosphateN-Acetyl-D-glucosamineAICA-riboside4-HydroxyprolineL-HistidinolVitamin C phosphatetrans-Aconitic acidPyruvic acidPyrrole-2-carboxylic acidGeranyl-PPN-AcetylglutamineN-Formylglycinecis,cis-Muconic acidQuinaldic acidGentisic acidGlycolic acidL-Tryptophan3-Methyladipic acidAcetoacetyl-CoANiacinamideDopamineSerotoninDeoxyuridineStearoyl-CoA4-Guanidinobutanoic aciddCMPCholesteroloctulose 8-phosphateIndole-3-propionic acidN-AcetylmannosamineL-ValineUracilIodotyrosineD-4'-PhosphopantothenateTryptamineN-AcetylserotoninL-KynurenineCreatineInosinic acidSphingosine 1-phosphateCaprylic acid2,4-DichlorophenolIDPD-2-Hydroxyglutaric acidCholesterol sulfateCytosineL-CystineN6-Methyladenosinealpha-Hydroxyisobutyric acidSpermineMyristic acidSuccinic acidHypoxanthinePhenyllactic acidDephospho-CoAGluconolactoneSelenomethionineNADPHL-Arginine3-Methylthiopropionic acidHippuric acid2-HydroxyglutarateCysteic acidAlpha-LactosePutrescine4-Hydroxycyclohexylcarboxylic acidHomovanillic acidL-CysteineL-Lactic acid2-Hydroxybutyric acidQuinolinic acidL-Glutamic acid2,4-Dihydroxypyrimidine-5-carboxylic acid2,3,4,5,6-Pentadeutero-L-phenylalaninHomocitrullineFADAdenineDeoxyadenosine triphosphateAcetyl-CoAThreonic acid2-HydroxyphenethylamineNicotinuric acidPalmitoleic acidCitraconic acidL-SerineInosinePurine1,2,3-Propanetricarboxylic acid3-Hydroxy-3-methylglutaryl-CoAHomocysteineDimethylglycine5-Aminoimidazole-4-carboxamideGlycyl-glycineDihydroxyacetone phosphatePanthenolCholic acidPalmitic acidBicine(R)-2-BenzylsuccinateCellobiosePhosphonoacetateAnserineUreidosuccinic acid4-Hydroxycinnamic acidN-alpha-Acetyl-L-lysinePhenylpropiolic acidTyramine4-Hydroxybenzoic acidN-Formyl-L-methionineVanillylmandelic acidDeoxyadenosineD-XylitolL-MethioninedCTPCiliatineGlycerophosphocholineTryptophanamide1-Aminocyclopropanecarboxylic acidOrotidylic acidPicolinic acid(2R,3R,4S,5R)-2-amino-3,4,5,6-tetrahydroxyhexanalmyo-InositolIndoleacetic acidPrephenate4-Hydroxy-3-methylbenzoic acidThyroxineMannitolPyroglutamic acidGlucose 1-phosphateCoenzyme A2-Aminobenzenesulfonic acidBetaine aldehydePyridoxamineGlucosamine 6-phosphateSalicylic acidN-Methylnicotinamide2-MethylguanosinePhosphoenolpyruvic acidLevulinic acidL-AcetylcarnitineN-AcetylputrescineXanthineS-AdenosylmethionineFructose 6-phosphateN-Acetyl-glucosamine 1-phosphateD-Sedoheptulose 7-phosphateDL-DopaDeoxyguanosineL-GlutamineQuinic acidUridine diphosphate glucuronic acidCholineLipoamideN-Acetyl-L-alanine2,4-Dihydroxybenzoic acidCytidine monophosphate2-Deoxy-D-glucopyranose 6-phosphate2-Ketohexanoic acid5-HydroxymethyluracilThymidineL-IsoleucineGlyceric acid 1,3-biphosphateOrotic acidall-trans-Retinoic acidMethylmalonic acidMalic acidAsymmetric dimethylarginine3-Phosphoglyceric acidLeucylalanine2,3-Diphosphoglyceric acidGluconic acidortho-Hydroxyphenylacetic acidPhosphorylcholine3-MethylindoleS-Adenosylhomocysteine2-Hydroxy-2-methylbutyric acidADP-glucoseL-Aspartic acid6-DimethylaminopurineGalacturonic acidProtoporphyrin IXN-Methyl-D-aspartic acidIsovalerylglycineMethionine sulfoxideAllantoic acid3,4-Dihydroxyhydrocinnamic acidTaurodeoxycholic acid4-Hydroxyphenylpyruvic acidCitramalic acidTrehalose 6-phosphate1,3-Dimethyluracil2-Aminobenzoic acidp-Aminobenzoic acidUridine triphosphateDeoxyadenosine monophosphateImidazoleacetic acidPhosphocreatineTartaric acidDeoxycholic acidN1-AcetylspermineIndole-3-carboxylic acidDL-O-PhosphoserineCarbamoyl phosphate(R)-Lipoic acid5-Hydroxy-L-tryptophan3-ChlorotyrosineBiopterinfalseLKB1 inactivation elicits a NNMT-mediated methyl sink and confers dependence on PRMT5 in lung cancerThe protein arginine methyl transferase 5 (PRMT5) emerges as a therapeutic target in S-methyl-5'-thioadenosine phosphorylase (MTAP)-deleted cancers, where MTA accumulation partially inhibits its activity. However, It remains unclear whether other genetic alterations can dictate PRMT5 activity in cancer. Here we identify LKB1 as an alternative predictor of PRMT5 inhibition in lung cancer independent of MTAP. Mechanistically, LKB1 loss activates SIK1/2-CRTC2 signaling to upregulate NNMT, creating a ""methyl sink"" that lowers the SAM/SAH ratio and attenuates PRMT5 activity. NNMT overexpression is sufficient to induce this hypomorphic PRMT5 state and heighten sensitivity to PRMT5 inhibitors. Functionally, PRMT5 inhibition induces senescence in LKB1-deficient cells and confers vulnerability to navitoclax, synergistically blunting tumor growth in vivo. Collectively, we identify PRMT5 as an actionable therapeutic vulnerability in LKB1-deficient lung cancer, and propose LKB1 status/NNMT expression as potential biomarkers for PRMT5 inhibition. These findings may expand the clinical utility of PRMT5-targeted therapies beyond MTAP-deleted cancers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