iProXProteomicsFengwei WangHomo Sapienshttp://www.iprox.org/page/project.html?id=IPX0006242000wangfengw@sysucc.org.cnSun Yat-sen University Cancer CenteriProXMetabolic dysregulation has been implicated as a key factor in colorectal cancer (CRC) initiation, however, the underlying driving forces and mechanisms remain poorly understood. Herein, transcriptome profiling of paired early-stage CRCs and adenomas identifies Nudix hydrolase 13 (NUDT13) as a critical suppressor. Elevated NUDT13 expression impedes the proliferation of CRC cells under hypoxic conditions and markedly inhibits CRC initiation by upregulating PKM1. Mechanistically, NUDT13 directly binds and stabilizes PKM1 protein by reducing its poly ADP-ribosylation (PARylation), which is catalyzed by PARP1 at E275/D281/E282/E285/D296, thereby inducing an oxidative phosphorylation (OXPHOS) phenotype in CRC cells. Moreover, spatiotemporal knockout of Nudt13 enhances intestinal tumorigenesis in mice, which can be significantly suppressed by PARP1 inhibitor Olaparib. Notably, residues E245/E248/E249 within the Nudix box motif of NUDT13 are essential for PKM1 PARylation, and a mimic peptide derived from this motif is sufficient to stabilize PKM1 protein and robustly inhibit CRC tumorigenesis. Collectively, this study reveals a previously unknown PARylation-dependent mechanism that regulates PKM1 protein stability and switches the metabolic pathway of CRC cells, providing a promising target for CRC treatment.Nudix Hydrolase 13 Impairs the Initiation of Colorectal Cancer by Inhibiting PKM1 ADP-Ribosylation.Lin Jinlong J, Yin Yixin Y, Cao Jinghua J, Zou Bingxu B, Han Kai K, Chen Yufan Y, Li Siyu S, Huang Cijun C, Chen Jiewei J, Lv Yongrui Y, Xu Shuidan S, Xie Dan D, Wang Fengwei FCoCL3., DLD-1, 4933433B15Rik, ligandADPRibosylation, Metabolic Networks, Networks, Colorectal Neoplasm, Nucleoside Diphosphates Linked to Moiety X Hydrolases, DmelCG40411, Adenomas, Laboratory, Mus domesticus, AZD 2281, Mono(ADP-Ribosyl)ation, CASP-14, protein, Tumor, F20O9_210, House Mouse, Monomorphic Adenomas, Transcript Expression Analysis, Adprt1, peptide, Polypeptides, Hydrolase, neutrophilic leucocyte, peptido, Oxidative, MARylations, neutrophil leukocyte, Gene Expression Monitorings, Poly-ADPRibosylation, Analysis, Profilings, protein aggregate, Fs(3)Hor, ADPRT, IKKg, Follicular, CG17696, KEY, Key, Atf4, Colorectal Tumors, 929, DmelCG8669, treatment, acinar cell adenoma (morphologic abnormality), DmelCG2684, Follicular Adenoma, Adprp, peptides, Analyses, ARTD1, Adenoma, ADPRT1, Adprt, AI893648, F20O9.210, DmGCSl, Pathways, Colorectal Carcinomas, Oncogeneses, Swiss Mice, CRUCIFERIN C, Nucleoside Diphosphates-Linked to Moiety-X Hydrolases, benign, Colorectal Tumor, NTef2, Microcystic Adenoma, large intestine cancer, Gene Expression Analysis, polymorphonuclear leukocyte, polynuclear neutrophilic leucocyte, Basal Cell Adenoma, Therapies, stage, Gcsl, GCSl, Poly-ADP-Ribosylation, Basal Cell Adenomas, somatic mutation, colorectal (colon or rectal) cancer, Tumors, Mono-ADPRibosylation, Lynparza, Papillary Adenomas, Therapy, Carcinoma, F16D14.16, MARylation, Pathway, OXPHOS, Poly ADP Ribosylations, ADP, potp, CASP14, mouse, Monitorings, pADPRT-1, Metabolic Network, F16D14_16, Poly(ADPRibosyl)ation, Fs(3)Sz11, Ribosylations, Gene Expression, DmIKKgamma, neutrocyte, PARP1, (ADP-Ribosyl)ation, dIKK, Mini-ICE, Kenny, MonoADPRibosylations, Colorectal Cancers, l(2)crc, anon-EST:fe3D7, Carcinomas, PARylations, Phosphorylation, Mus musculus, cruciferin 3, Poly ADPRibosylation, Caspase-14 subunit p10, Transcriptome Profilings, acinar cell adenoma, mice, susceptibility to, IKK-gamma, Swiss Mouse, ADPRibosylations, ADP Ribosylation, Caspase-14 subunit p19, MICE, cancer of large bowel, Treatments, early, domesticus, ATF-4, Papillary, CG17718, Phenotypes, MonoADPRibosylation, Mono-ADP-Ribosylation, DmelCG16910, Gene Expression Analyses, Oncogenesis, antagonists and inhibitors, Horka, ADPRT 1, Protein Stabilities, CG2684, cancer of the large bowel, Fs(3)Horka, CG8669, Follicular Adenomas, Trabecular Adenoma, Expression Analysis, Mouse, Polypeptide, cancer of large intestine, mKIAA0147, ATF4/crc, 5830444G22Rik, AI118201, CRCS, 3.4.22.-, polynuclear neutrophilic leukocyte, Tumorigeneses, Colorectal Cancer, Clr, Trabecular Adenomas, Neoplasms, LD21673.3prime, developmental stage, adenoma, DmelCG4919, Gene, mini-ICE, BEST:LD21673, Network, AZD221, protein-containing complex, autosomal dominant, dIKK-gamma, Microcystic, Gene Expression Profilings, Colorectal, colorectal cancer, AZD-2281, Stability, mRNA Differential Displays, Gene Expression Pattern Analysis, Monomorphic, Mono, CG40411, dATF-4, House, DmIKK-gamma, Gene Products, Mono ADPRibosylations, Mus musculus domesticus, Mono ADP Ribosylation, anon-EST:Liang-2.17, anon-EST:Liang-2.11, DmF2, dmIKKgamma, clone 2.11, IKK[[gamma]], C80510, Mice, AZD2281, (ADPRibosyl)ation, PARylation, lod, study, Nudix Proteins, Microcystic Adenomas, clone 2.17, Swiss, neutrophil leucocyte, Scrb1, CG9429, inhibiteur, Transcriptomics, Ire1, Transcript Expression, Transcriptome Analysis, neutrophilic leukocyte, adprt1, respiratory-chain phosphorylation, GCLm, Monitoring, cancer of the large intestine, ADP Ribosylations, Oxidative Phosphorylations, inhibidor, IKK, vartul, Poly ADP, peptidos, 4919, Expression Analyses, parp-1, Cancer, Poly-ADP-Ribosylations, poly(ADP-ribose) polymerase 1, inhibitors, Profiling, CG4919, Transcriptome, PolyADPRibosylation, Basal Cell, protein complex, SCRIB1, Proteins, Phosphorylations, inhibitor, eth, Tumorigenesis, Nudix Hydrolase, motif, Ribosylation, Cell, ATPARP1, Peptide, Stabilities, Differential Display, polypeptide, IKKgamma, disease management., Transcript Expression Analyses, native protein, Mus, sPARP-1, DmGCLM, Protein, Trabecular, Neoplasm, CRC, Crc, 4933433B15Rik, mRNA Differential Display, Mono(ADPRibosyl)ation, Metabolic Pathways, Poly-ADPRibosylations, antagonists, large bowel cancer, Mono ADPRibosylation, Gene Expression Monitoring, Transcriptome Profiling, mRNA, Poly, PARP, box, Metabolic, Dmikkgamma, Nudix, ADP-Ribosylations, Colorectal Carcinoma, Monomorphic Adenoma, Carcinogeneses, crc, House Mice, Cancers, CRIB, Differential Displays, CG16910, Lds, parp, Transcriptome Analyses, CG17685, Mono-ADP-Ribosylations, Mono-ADPRibosylations, Laboratory Mice, macromolecular stability of protein, Protein Gene Products, DmelCG9429, Gene Proteins, Parp-1, crt, colon cancer, padprt-1, ppol, Therapeutic, Papillary Adenoma, PARP-1, D.PARP, PMN, polymorphonuclear leucocyte, Metabolic Pathway, Peptid, Treatment, dPARP, PolyADPRibosylations, Dm.pARTa, poly, PPOL, Laboratory Mouse, polymorphonuclear neutrophil, Poly(ADP-Ribosyl)ationADPRibosylation, Nucleoside Diphosphates Linked to Moiety X Hydrolases, Colorectal Neoplasm, Carcinoma, MARylation, Colorectal Cancer, ADP, Neoplasms, Mono(ADP-Ribosyl)ation, Tumor, Nudix Hydrolase, autosomal dominant, Ribosylation, Ribosylations, Colorectal, colorectal cancer, Hydrolase, (ADP-Ribosyl)ation, Mono, MARylations, Neoplasm, Mono ADPRibosylations, Mono ADP Ribosylation, MonoADPRibosylations, CRC, Colorectal Cancers, Mono(ADPRibosyl)ation, (ADPRibosyl)ation, Colorectal Tumors, Carcinomas, large bowel cancer, Mono ADPRibosylation, Nudix Proteins, Nudix, ADP-Ribosylations, susceptibility to, Mono-ADPRibosylations., Colorectal Carcinoma, ADPRibosylations, Colorectal Carcinomas, ADP Ribosylation, Nucleoside Diphosphates-Linked to Moiety-X Hydrolases, Cancers, Colorectal Tumor, cancer of large bowel, large intestine cancer, Mono-ADP-Ribosylations, cancer of the large intestine, MonoADPRibosylation, Mono-ADP-Ribosylation, colon cancer, ADP Ribosylations, cancer of the large bowel, cancer of large intestine, somatic mutation, colorectal (colon or rectal) cancer, Tumors, Cancer, Mono-ADPRibosylationliquid chromatography tandem mass spectroscopy, LC-MS2, DLD-1, Co-Immunoprecipitations, Clr, determination, SCRIB1, potp, LC-MS/MS, eth, F20O9_210, autosomal dominant, LC-MS-MS, Concept, Co Immunoprecipitation, colorectal cancer, LC/MS/MS, Role Concept, dATF-4, Roles, LC-MSMS, Role, Immune Precipitations, Concepts, anon-EST:Liang-2.17, 4933433B15Rik, Crc, anon-EST:Liang-2.11, CRC, clone 2.11, l(2)crc, anon-EST:fe3D7, Immune Precipitation, CoCL3, Atf4, 929, DmelCG8669, large bowel cancer, cruciferin 3, LCMSMS, clone 2.17, susceptibility to, Co-Immunoprecipitation, Scrb1, CG9429, F20O9.210, Precipitation, chemical analysis., crc, CRUCIFERIN C, CRIB, Ire1, cancer of large bowel, large intestine cancer, cancer of the large intestine, ATF-4, DmelCG9429, crt, colon cancer, Immune, liquid chromatography-tandem mass spectroscopy, vartul, Role Concepts, cancer of the large bowel, CG8669, liquid chromatography tandem mass spectrometry, assay, cancer of large intestine, Precipitations, mKIAA0147, ATF4/crc, somatic mutation, AI118201, colorectal (colon or rectal) cancerfalsePotential binding partners of NUDT13 in DLD-1To explore the role of NUDT13 in the initiation and progression of CRC, we performed NUDT13 immunoprecipitation in DLD-1 following LC-MS/MS analysis.Sat Apr 08 00:00:00 GMT+01:00 2023PXD041430960639921866