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Wong YK, Wang J, Lim TK, Lin Q, Yap CT, Shen HM. O-GlcNAcylation promotes fatty acid synthase activity under nutritional stress as a pro-survival mechanism in cancer cells. Proteomics 2022 22(9) 35083852
Abstract:
Protein O-GlcNAcylation is a specific form of protein glycosylation that targets a wide range of proteins with important functions. O-GlcNAcylation is known to be deregulated in cancer and has been linked to multiple aspects of cancer pathology. Despite its ubiquity and importance, the current understanding of the role of O-GlcNAcylation in the stress response remains limited. In this study, we performed a quantitative chemical proteomics-based open study of the O-GlcNAcome in HeLa cells, and identified 163 differentially-glycosylated proteins under starvation, involving multiple metabolic pathways. Among them, fatty acid metabolism was found to be targeted and subsequent analysis confirmed that fatty acid synthase (FASN) is O-GlcNAcylated. O-GlcNAcylation led to enhanced de novo fatty acid synthesis (FAS) activity, and fatty acids contributed to the cytoprotective effects of O-GlcNAcylation under starvation. Moreover, dual inhibition of O-GlcNAcylation and FASN displayed a strong synergistic effect in vitro in inducing cell death in cancer cells. Together, the results from this study provide novel insights into the role of O-GlcNAcylation in the nutritional stress response and suggest the potential of combining inhibition of O-GlcNAcylation and FAS in cancer therapy.
O-GlcNAc proteins:
RUXGL, ADAS, DX39A, MYO1C, IPO5, PESC, NOP56, DDX3X, SCD, MGST3, HNRDL, XPO1, SURF4, OGT1, PPM1G, MOT4, DHX15, CYB5B, SERA, HNRPR, BUB3, ACTN4, MYO1B, GANP, HNRPQ, NDUS7, MPU1, H2AY, FLNB, SC22B, SF3B1, U520, UTP20, NU155, ATP5H, RL1D1, MTA2, RTN3, VAPB, IPO7, ACSL3, BAG2, TOM40, LDHA, DHE3, AATM, PGK1, ASSY, LMNA, TFR1, ALDOA, K2C1, G3P, HSPB1, RPN1, AT1A1, ADT2, PCCA, RLA1, RLA0, LA, K1C18, K2C8, ATPB, ENOA, NPM, TPM3, LDHB, PDIA1, ANXA2, TBB5, TRY1, PROF1, SYEP, HS90A, HNRPC, DAF, 4F2, HS90B, ODPA, RU17, VIME, RS17, K2C7, GNAI3, RSSA, LEG1, ROA1, PARP1, PRS56, HS71B, ODP2, THIO, MGST1, CH60, BIP, HSP7C, GTR1, TOP2A, PYC, PABP1, PCNA, ADT3, IMDH2, KCRU, XRCC6, XRCC5, EF2, K1C10, K2C5, PDIA4, PLST, ETFA, MIF, KPYM, ENPL, HNRPL, PLAK, EZRI, NDKA, RS2, DESP, H13, NCPR, AT2A2, DDX5, TCPA, PTN1, ARF4, RL7, RL17, NUCL, GSTM3, FLNA, FBRL, PUR6, UBA1, ROA2, QCR2, SFPQ, PPIB, RS3, SAHH, COF1, MCM3, RS12, ATPA, U2AF2, RL13, S10A4, PTBP1, SYVC, EF1G, STOM, RL10, APEX1, PYR1, CALX, TKT, ERP29, PRDX6, PRDX5, PRDX3, RL12, PDIA3, CPSM, HNRH1, STIP1, L1CAM, PRDX2, P5CR1, DUT, MCM7, GLYM, HSP74, PHB1, RL22, MYH9, SOAT1, DEK, K22E, RL4, LONM, NUP62, GRP75, IF4A3, RL3, RL13A, ARL1, STAT3, MDHM, RFC3, ECHA, SYIC, LAP2A, LPPRC, MATR3, MSH2, GPDM, VDAC2, KI67, BAG6, RL27A, RL5, RS9, STT3A, CAPZB, SYQ, RL29, AT5G3, TCPE, RL34, FAS, TCPG, EFTU, ACADV, TMEDA, NU153, RBP2, CPT1A, SERPH, RL14, TCPQ, TCPD, FXR1, RAB5C, RAB7A, HCFC1, ROA3, 6PGD, HNRPM, IMA1, HNRPF, MSH6, TXTP, ACLY, COPA, MOT1, SYRC, KAD2, P5CS, XPO2, TERA, NP1L1, DSRAD, ATPK, TMM33, TPIS, MYL6, IF4A1, RS20, S10AA, RAP1B, RL15, RL37A, HNRPK, RS8, RS16, 1433E, RS14, RS23, RS11, RUXE, RL7A, RS4X, RS6, H4, RAB1A, RAN, RL23, RS25, RS26, RL10A, RL11, RL8, PPIA, RS27A, RSMN, RACK1, ACTG, UBC9, TBA1B, TBB4B, GTF2I, TCPB, PRKDC, RL24, ARF5, RL19, SRSF3, MPCP, CLH1, HNRPU, SPTB2, EXOSX, RL18A, RL6, IF4G1, K1C17, PRDX1, RL18, C1QBP, KHDR1, DHX9, NCBP1, AHNK, NU160, SF3A3, ILF3, ACACA, PRDX4, CBX3, TIF1B, SPTN1, HNRPD, SAFB2, TTL12, CAPR1, ITPR1, RRP1B, GANAB, LBR, GOGB1, IMB1, NUMA1, SUZ12, U5S1, RRS1, PDIA6, PLEC, TEBP, NONO, PCBP1, PCBP2, DHC24, SF3B3, SF3A1, TRAM1, ELAV1, AAAT, RBBP7, H31T, PDS5A, TSR1, IF2GL, RRP12, NU188, HP1B3, EF1A3, PPR18, PRP8, C1TM, DHX30, CAND1, MISP, SPB1, PELP1, RDH10, CCAR2, TXND5, STT3B, BRX1, PO210, GEMI5, RT27, HS105, GCN1, NU205, AKAP1, AN32B, RBP56, DDX17, FUBP2, TNPO1, UBP7, UTP4, LRC59, PGAM5, FUBP3, MBOA7, MCCA, WRIP1, UHRF1, POP1, HCD2, ROAA, TM9S2, TCPH, ANM1, H2B1L, RNZ2, MEP50, MBB1A, ESYT1, H2AJ, GNL3, HDHD5, GTPB4, API5, RPF2, SFXN1, RDH14, ABCB6, DDX21, MDN1, DCA13, ATD3A, DDX18, MIC19, TEX10, TECR, MYOF, THYN1, HACD3, RRBP1, ABC3B, RLP24, ACINU, OGDHL, COR1C, PRP19, SSRG, TRI33, EIF3L, RUVB1, VDAC3, PDIP2, NOP58, SF3B6, RTCB, RL36, LAS1L, SRPRB, COPG1, MTCH2, CEPT1, ZNT1
Species: Homo sapiens
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Liu Y, Chen Q, Zhang N, Zhang K, Dou T, Cao Y, Liu Y, Li K, Hao X, Xie X, Li W, Ren Y, Zhang J. Proteomic profiling and genome-wide mapping of O-GlcNAc chromatin-associated proteins reveal an O-GlcNAc-regulated genotoxic stress response. Nature communications 2020 11(1) 33214551
Abstract:
O-GlcNAc modification plays critical roles in regulating the stress response program and cellular homeostasis. However, systematic and multi-omics studies on the O-GlcNAc regulated mechanism have been limited. Here, comprehensive data are obtained by a chemical reporter-based method to survey O-GlcNAc function in human breast cancer cells stimulated with the genotoxic agent adriamycin. We identify 875 genotoxic stress-induced O-GlcNAc chromatin-associated proteins (OCPs), including 88 O-GlcNAc chromatin-associated transcription factors and cofactors (OCTFs), subsequently map their genomic loci, and construct a comprehensive transcriptional reprogramming network. Notably, genotoxicity-induced O-GlcNAc enhances the genome-wide interactions of OCPs with chromatin. The dynamic binding switch of hundreds of OCPs from enhancers to promoters is identified as a crucial feature in the specific transcriptional activation of genes involved in the adaptation of cancer cells to genotoxic stress. The OCTF nuclear factor erythroid 2-related factor-1 (NRF1) is found to be a key response regulator in O-GlcNAc-modulated cellular homeostasis. These results provide a valuable clue suggesting that OCPs act as stress sensors by regulating the expression of various genes to protect cancer cells from genotoxic stress.
O-GlcNAc proteins:
RBM47, SBNO1, CNOT1, RGPD3, P121C, PDLI1, MYO1C, AIP, PSD11, PGRC1, TAF4, CLIC1, IPO5, IF2B3, AGRIN, PLOD2, HMGN4,