{"doi":"10.1172/jci190989","title":"A distinct mechanism of epigenetic reprogramming silences PAX2 and initiates endometrial carcinogenesis","abstract":"Functional inactivation of tumor suppressor genes drives cancer initiation, progression, and treatment responses. Most tumor suppressor genes are inactivated through 1 of 2 well-characterized mechanisms: DNA-level mutations, such as point mutations or deletions, and promoter DNA hypermethylation. Here, we report a distinct third mechanism of tumor suppressor inactivation based on alterations to the histone rather than DNA code. We demonstrated that PAX2 is an endometrial tumor suppressor recurrently inactivated by a distinct epigenetic reprogramming event in more than 80% of human endometrial cancers. Integrative transcriptomic, epigenomic, 3D genomic, and machine learning analyses showed that PAX2 transcriptional downregulation is associated with replacement of open/active chromatin features (H3K27ac/H3K4me3) with inaccessible/repressive chromatin features (H3K27me3) in a framework dictated by 3D genome organization. The spread of the repressive H3K27me3 signal resembled a pearl necklace, with its length modulated by cohesin loops, thereby preventing transcriptional dysregulation of neighboring genes. This mechanism, involving the loss of a promoter-proximal superenhancer, was shown to underlie transcriptional silencing of PAX2 in human endometrial cancers. Mouse and human preclinical models established PAX2 as a potent endometrial tumor suppressor. Functionally, PAX2 loss promoted endometrial carcinogenesis by rewiring the transcriptional landscape via global enhancer reprogramming. The discovery that most endometrial cancers originate from a recurring epigenetic alteration carries profound implications for their diagnosis and treatment.","journal":"Journal of Clinical Investigation","year":2025,"id":514879,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9488,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":318289,"name":"Susmita G. Ramanand","orcid":"0000-0001-9711-0342","position":1,"is_corresponding":false},{"id":466080,"name":"Ileana Cuevas","orcid":"0000-0002-6250-375X","position":2,"is_corresponding":false},{"id":318296,"name":"Yunpeng Gao","orcid":"0000-0003-4746-4614","position":3,"is_corresponding":false},{"id":521065,"name":"Sora Lee","orcid":"0000-0002-0075-7324","position":4,"is_corresponding":false},{"id":994194,"name":"Ahmed K. Abbas","orcid":"0000-0002-3233-3008","position":5,"is_corresponding":false},{"id":1079522,"name":"Xunzhi Zhang","orcid":"0000-0002-3599-1751","position":6,"is_corresponding":false},{"id":473431,"name":"Vinod Kumar","orcid":"0000-0002-0086-7398","position":7,"is_corresponding":false},{"id":466084,"name":"Prasad Koduru","orcid":"0000-0001-7109-5906","position":8,"is_corresponding":false},{"id":339678,"name":"Sambit Roy","orcid":"0000-0001-9496-5572","position":9,"is_corresponding":false},{"id":13295,"name":"Russell R. Broaddus","orcid":"0000-0002-8692-273X","position":10,"is_corresponding":false},{"id":465346,"name":"Victoria Bae‐Jump","orcid":"0000-0001-6778-0951","position":11,"is_corresponding":false},{"id":748098,"name":"Andrew B. Gladden","orcid":"0000-0003-4519-5510","position":12,"is_corresponding":false},{"id":607655,"name":"Jayanthi Lea","orcid":"0000-0002-8657-4309","position":13,"is_corresponding":false},{"id":1359749,"name":"Elena Lucas","orcid":"0000-0002-7930-1089","position":14,"is_corresponding":false},{"id":240348,"name":"Chao Xing","orcid":"0000-0002-1838-0502","position":15,"is_corresponding":false},{"id":1359750,"name":"Akio Kobayashi","orcid":"0000-0001-5731-9600","position":16,"is_corresponding":false},{"id":318299,"name":"Ram S. Mani","orcid":"0000-0003-3552-7905","position":17,"is_corresponding":false},{"id":236561,"name":"Diego H. Castrillón","orcid":"0000-0001-6690-4633","position":18,"is_corresponding":false},{"id":466081,"name":"Subhransu S. Sahoo","orcid":"0000-0003-2946-0484","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T02:48:34.431522Z","pmid":"40829174","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":[]}