{"doi":"10.1016/j.jcmgh.2021.09.014","title":"KDM6A Regulates Cell Plasticity and Pancreatic Cancer Progression by Noncanonical Activin Pathway","abstract":"BACKGROUND & AIMS: Inactivating mutations of KDM6A, a histone demethylase, were frequently found in pancreatic ductal adenocarcinoma (PDAC). We investigated the role of KDM6A (lysine demethylase 6A) in PDAC development. METHODS: , and orthotopic xenograft mice to investigate the impacts of Kdm6a deficiency on pancreatic tumorigenesis and pancreatitis. RESULTS: Loss of KDM6A was associated with metastasis in PDAC patients. Bromouridine sequencing analysis showed up-regulation of the epithelial-mesenchymal transition pathway in PDAC cells deficient in KDM6A. Loss of KDM6A promoted mesenchymal morphology, migration, and invasion in PDAC cells in vitro. Mechanistically, activin A and subsequent p38 activation likely mediated the role of KDM6A loss. Inhibiting either activin A or p38 reversed the effect. Pancreas-specific Kdm6a-knockout mice pancreata showed accelerated PDAC progression, developed a more aggressive undifferentiated type of PDAC, and increased metastases in the background of Kras and p53 mutations. Kdm6a-deficient pancreata in a pancreatitis model had a delayed recovery with increased PDAC precursor lesions compared with wild-type pancreata. CONCLUSIONS: Loss of KDM6A accelerates PDAC progression and metastasis, most likely by a noncanonical p38-dependent activin A pathway. KDM6A also promotes pancreatic tissue recovery from pancreatitis. Activin A might be used as a therapeutic target for KDM6A-deficient PDACs.","journal":"Cellular and Molecular Gastroenterology and Hepatology","year":2021,"id":159095,"datarank":0.5676284450877392,"base_score":3.784189633918261,"endowment":3.784189633918261,"self_citation_contribution":0.5676284450877392,"citation_network_contribution":0.0,"self_endowment_contribution":0.5676284450877392,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":43,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9659,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":670077,"name":"Shanqiao Wei","orcid":null,"position":1,"is_corresponding":false},{"id":656401,"name":"Lin Jin","orcid":"0000-0001-6403-7097","position":2,"is_corresponding":false},{"id":669291,"name":"Sivakumar Jeyarajan","orcid":"0000-0001-6614-5489","position":3,"is_corresponding":false},{"id":669292,"name":"Jing Yang","orcid":"0000-0002-4902-7971","position":4,"is_corresponding":false},{"id":669293,"name":"Yumei Gu","orcid":"0000-0003-1050-4379","position":5,"is_corresponding":false},{"id":656402,"name":"Hong Sun Kim","orcid":"0000-0002-1856-1952","position":6,"is_corresponding":false},{"id":669294,"name":"Shula Schechter","orcid":"0000-0001-9202-5405","position":7,"is_corresponding":false},{"id":669295,"name":"Shuang Lu","orcid":"0000-0001-6434-2454","position":8,"is_corresponding":false},{"id":376382,"name":"Michelle T. Paulsen","orcid":"0000-0002-8090-0118","position":9,"is_corresponding":false},{"id":260368,"name":"Karan Bedi","orcid":"0000-0002-7843-738X","position":10,"is_corresponding":false},{"id":669296,"name":"Ishwarya Venkata Narayanan","orcid":"0000-0002-4666-027X","position":11,"is_corresponding":false},{"id":260370,"name":"Mats Ljungman","orcid":"0000-0003-1553-6695","position":12,"is_corresponding":false},{"id":225419,"name":"Howard C. Crawford","orcid":"0000-0001-9360-3019","position":13,"is_corresponding":false},{"id":225422,"name":"Marina Pasca di Magliano","orcid":"0000-0001-9632-9035","position":14,"is_corresponding":false},{"id":245525,"name":"Kai Ge","orcid":"0000-0002-7442-5138","position":15,"is_corresponding":false},{"id":246400,"name":"Yali Dou","orcid":"0000-0002-4040-1429","position":16,"is_corresponding":false},{"id":88874,"name":"Jiaqi Shi","orcid":"0000-0003-4893-1587","position":17,"is_corresponding":false},{"id":669290,"name":"Zhujun Yi","orcid":"0000-0003-3142-8715","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:44:35.165422Z","pmid":"34583087","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":[]}