{"doi":"10.47248/chp2502020008","title":"A Hierarchy of Luminal Transcription Factors Defines AR Cistrome and Is Lost in Neuroendocrine Prostate Cancer","abstract":"Androgen receptor (AR) is a hormonal transcription factor (TF) that binds to cis-regulatory elements of prostate lineage-specific genes to govern androgen response and progression of prostate cancer (PCa). This AR cistrome has been reported to be controlled by multiple chromatin-pioneering factors such as FOXA1, HOXB13, and GATA2. However, how these pioneer factors cooperate to regulate the AR cistrome remains unclear. Here, through comparative ChIP-seq analyses, we found that FOXA1 alone was sufficient to recruit AR to its binding sites regardless of H3K4me1. FOXA1 further enlisted HOXB13 and/or GATA2 to augment AR binding and enhancer activation, while HOXB13 and/or GATA2 alone were unable to recruit each other, nor AR. Moreover, HOXB13 knockdown attenuated AR and GATA2 expression and chromatin binding but failed to reprogram their cistromes, suggesting a role as a cofactor rather than a pioneer factor. During the neuroendocrine transformation (NET) of PCa, AR, GATA2, and HOXB13 were lost due to promoter hypermethylation, whereas FOXA1 was down-regulated by transcriptional repression. Lastly, through analyses of tissue microarrays, we confirmed that FOXA1 protein levels were drastically reduced in neuroendocrine PCa, as compared to AR-positive PCa. Therefore, our findings report a hierarchical network of TFs, pioneered by FOXA1 and facilitated by HOXB13 and GATA2, that defines lineage-specific AR cistrome and was lost during NET of PCa.","journal":"Cancer Heterogeneity and Plasticity","year":2025,"id":552664,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9482,"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":801184,"name":"Xiaodong Lü","orcid":"0000-0003-4731-0762","position":1,"is_corresponding":false},{"id":1365446,"name":"Lourdes Brea","orcid":"0000-0001-9727-7185","position":2,"is_corresponding":false},{"id":579695,"name":"Xianglin Shi","orcid":"0000-0001-9512-7570","position":3,"is_corresponding":false},{"id":511247,"name":"Jindan Yu","orcid":"0000-0002-2326-0409","position":4,"is_corresponding":false},{"id":817999,"name":"Jonathan C. Zhao","orcid":"0000-0002-3163-380X","position":5,"is_corresponding":false},{"id":1449026,"name":"Viriya Keo","orcid":"0000-0002-3256-5992","position":0,"is_corresponding":true}],"reference_count":36,"raw_metadata":null,"created_at":"2026-07-19T02:54:37.527189Z","pmid":"41768226","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":[]}