{"doi":"10.3390/cancers15194742","title":"Critical Role of Novel O-GlcNAcylation of S550 and S551 on the p65 Subunit of NF-κB in Pancreatic Cancer","abstract":"Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with a mere 5-year survival of ~10%. This highlights the urgent need for innovative treatment options for PDAC patients. The nuclear factor κB (NF-κB) is a crucial transcription factor that is constitutively activated in PDAC. It mediates the transcription of oncogenic and inflammatory genes that facilitate multiple PDAC phenotypes. Thus, a better understanding of the mechanistic underpinnings of NF-κB activation holds great promise for PDAC diagnosis and effective therapeutics. Here, we report a novel finding that the p65 subunit of NF-κB is O-GlcNAcylated at serine 550 and 551 upon NF-κB activation. Importantly, the overexpression of either serine-to-alanine (S-A) single mutant (S550A or S551A) or double mutant (S550A/S551A) of p65 in PDAC cells impaired NF-κB nuclear translocation, p65 phosphorylation, and transcriptional activity, independent of IκBα degradation. Moreover, the p65 mutants downregulate a category of NF-κB-target genes, which play a role in perpetuating major cancer hallmarks. We further show that overexpression of the p65 mutants inhibited cellular proliferation, migration, and anchorage-independent growth of PDAC cells compared to WT-p65. Collectively, we discovered novel serine sites of p65 O-GlcNAcylation that drive NF-κB activation and PDAC phenotypes, thus opening new avenues by inhibiting the NF-κB O-GlcNAcylation enzyme, O-GlcNAc transferase (OGT), for PDAC treatment in the future.","journal":"Cancers","year":2023,"id":341679,"datarank":0.5094142238919697,"base_score":2.833213344056216,"endowment":2.833213344056216,"self_citation_contribution":0.42498200160843247,"citation_network_contribution":0.08443222228353724,"self_endowment_contribution":0.42498200160843247,"citer_contribution":0.08443222228353724,"corpus_percentile":null,"corpus_rank":null,"citation_count":16,"citer_count":16,"citers_with_citation_signal":7,"citers_with_endowment":7,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9595,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":465315,"name":"Matthew Martin","orcid":"0000-0002-3961-5809","position":1,"is_corresponding":false},{"id":293631,"name":"Benlian Wang","orcid":null,"position":2,"is_corresponding":false},{"id":292113,"name":"Guanglong Jiang","orcid":"0000-0002-9233-052X","position":3,"is_corresponding":false},{"id":1074986,"name":"Faranak Alipourgivi","orcid":"0000-0003-2583-8953","position":4,"is_corresponding":false},{"id":400731,"name":"Xiumei Huang","orcid":"0000-0002-7306-0288","position":5,"is_corresponding":false},{"id":470623,"name":"Ahmad R. Safa","orcid":null,"position":6,"is_corresponding":false},{"id":227678,"name":"Yunlong Liu","orcid":"0000-0002-2699-626X","position":7,"is_corresponding":false},{"id":292117,"name":"Tao Lu","orcid":"0000-0002-0013-4987","position":8,"is_corresponding":false},{"id":465314,"name":"Aishat Motolani","orcid":"0000-0002-5909-3446","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:11:08.077724Z","pmid":"37835439","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}