{"id":{"repo_id":"iupui","oai_identifier":"oai:scholarworks.indianapolis.iu.edu:1805/42036"},"canonical_url":"https://search.dev.ndltd.org/etd/iupui/oai:scholarworks.indianapolis.iu.edu:1805/42036","repository":{"repo_id":"iupui","name":"IUPUI","base_url":"https://scholarworks.indianapolis.iu.edu/server/oai/request"},"display":{"title":"Dissecting the Role of Novel O-GlcNAcylation 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 PDAC cellular proliferation, migration, and anchorage-independent growth compared to WT-p65. We also show that inhibition of NF-κB O-GlcNAcylation may mitigate gemcitabine resistance and enhance its efficacy in PDAC cells. Collectively, our study uncovers a novel aspect of NF-κB regulation, which could aid future therapeutic development by targeting O-GlcNAc transferase (OGT) in pancreatic cancer.","abstract_html":"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 PDAC cellular proliferation, migration, and anchorage-independent growth compared to WT-p65. We also show that inhibition of NF-κB O-GlcNAcylation may mitigate gemcitabine resistance and enhance its efficacy in PDAC cells. Collectively, our study uncovers a novel aspect of NF-κB regulation, which could aid future therapeutic development by targeting O-GlcNAc transferase (OGT) in pancreatic cancer.","abstract_has_math":false,"creators":["Motolani, Aishat Abiola"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Lu, Tao"],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-06","date_published":"2024-06","updated_at":"2026-07-24T02:40:24Z","subjects":["NF-κB","O-GlcNAcylation","pancreatic cancer","post-translational modification"],"languages":["en_US"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://doi.org/10.7912/DTYS-3T16"],"render_values":[{"text":"https://doi.org/10.7912/DTYS-3T16","href":"https://doi.org/10.7912/DTYS-3T16","code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/1805/42036","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Lu, Tao"]},{"key":"dc:contributor.other","label":"Dc Contributor Other","values":["Safa, Ahmad","Dong, Charlie","Pollok, Karen","Corson, Timothy"]},{"key":"dc:creator","label":"Author","values":["Motolani, Aishat Abiola"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2024-07-08T10:29:43Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2024-07-08T10:29:43Z"]},{"key":"dc:date.issued","label":"Date","values":["2024-06"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["NF-κB","O-GlcNAcylation","pancreatic cancer","post-translational modification"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en_US"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/1805/42036","https://doi.org/10.7912/DTYS-3T16"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Indiana University-Purdue University Indianapolis (IUPUI)"]},{"key":"dc:description.abstract","label":"Abstract","values":["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 PDAC cellular proliferation, migration, and anchorage-independent growth compared to WT-p65. We also show that inhibition of NF-κB O-GlcNAcylation may mitigate gemcitabine resistance and enhance its efficacy in PDAC cells. Collectively, our study uncovers a novel aspect of NF-κB regulation, which could aid future therapeutic development by targeting O-GlcNAc transferase (OGT) in pancreatic cancer."]},{"key":"dc:title","label":"Title","values":["Dissecting the Role of Novel O-GlcNAcylation of NF-κB in Pancreatic Cancer"]}]}],"canonical_facts":{"dc:contributor.advisor":["Lu, Tao"],"dc:contributor.other":["Safa, Ahmad","Dong, Charlie","Pollok, Karen","Corson, Timothy"],"dc:creator":["Motolani, Aishat Abiola"],"dc:date.accessioned":["2024-07-08T10:29:43Z"],"dc:date.available":["2024-07-08T10:29:43Z"],"dc:date.issued":["2024-06"],"dc:description":["Indiana University-Purdue University Indianapolis (IUPUI)"],"dc:description.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 PDAC cellular proliferation, migration, and anchorage-independent growth compared to WT-p65. We also show that inhibition of NF-κB O-GlcNAcylation may mitigate gemcitabine resistance and enhance its efficacy in PDAC cells. Collectively, our study uncovers a novel aspect of NF-κB regulation, which could aid future therapeutic development by targeting O-GlcNAc transferase (OGT) in pancreatic cancer."],"dc:identifier.uri":["https://hdl.handle.net/1805/42036","https://doi.org/10.7912/DTYS-3T16"],"dc:language.iso":["en_US"],"dc:subject":["NF-κB","O-GlcNAcylation","pancreatic cancer","post-translational modification"],"dc:title":["Dissecting the Role of Novel O-GlcNAcylation of NF-κB in Pancreatic Cancer"],"dc:type":["Thesis"]},"updated_at":"2026-07-24T02:40:24Z"}