{"doi":"10.1186/s12967-023-04429-4","title":"Dissecting transcription of the 8q24-MYC locus in prostate cancer recognizes the equilibration between androgen receptor direct and indirect dual-functions","abstract":"BACKGROUND: Androgen receptor (AR) activation and repression dual-functionality only became known recently and still remains intriguing in prostate cancer (PCa). MYC is a prominent oncogene that functionally entangles with AR signaling in PCa. Further exploration of AR regulatory mechanisms on MYC gene transcription bears clinical and translation significance. METHODS: Bioinformatics analysis of PCa cell line and clinical RNA-Seq and ChIP-Seq (chromatin immunoprecipitation-sequencing) datasets to anchor interactions of AR and MYC transcriptional networks. ChIP-qPCR and 3C (chromosome conformation capture) analyses to probe MYC distal regulation by AR binding sites (ABSs). CRISPR/Cas9-mediated genome-editing to specify functions of ABS within the 8q24-MYC locus on androgen-mediated MYC transcription. Global FoxA1 and HoxB13 distribution profiling to advance AR transcriptional mechanisms. RESULTS: Here we recognize AR bi-directional transcription mechanisms by exploiting the prominent 8q24-MYC locus conferring androgen hyper-sensitivity. At ~ 25 Kb downstream of the MYC gene, we identified an undefined ABS, P10. By chromatin analyses, we validated androgen-dependent spatial interaction between P10 and MYC-Promoter (MYC-Pro) and temporal epigenetic repression of these MYC-proximal elements. We next designed a CRISPR/Cas9-mediated double genomic knock-out (KO) strategy to show that P10-KO slightly lessened androgen-elicited MYC transrepression in LNCaP-AR cells. In similar genomic editing assays, androgen-mediated MYC repression became slightly deepened upon KO of P11, an ABS in the PVT1 gene locus highly enriched in AR-binding motifs and peaks. We also investigated multiple ABSs in the established PCAT1 super-enhancer that distally interacts with MYC-Pro for transactivation, with each KO pool consistently shown to relieve androgen-elicited MYC repression. In the end, we systemically assessed androgen effects in the 8q24-MYC locus and along PCa genome to generalize H3K27ac and BRD4 re-distribution from pioneer factors (FoxA1 and HoxB13) to AR sites. CONCLUSION: Together, we reconciled these observations by unifying AR dual-functions that are mechanistically coupled to and equilibrated by co-factor redistribution.","journal":"Journal of Translational Medicine","year":2023,"id":356729,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9588,"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":1105791,"name":"Zhao Wei","orcid":"0009-0002-2554-4031","position":1,"is_corresponding":false},{"id":1105792,"name":"Tianwei Jia","orcid":"0009-0007-1931-9010","position":2,"is_corresponding":false},{"id":645040,"name":"Liyang Wang","orcid":"0009-0007-5252-8092","position":3,"is_corresponding":false},{"id":1106281,"name":"Nuosu Nama","orcid":null,"position":4,"is_corresponding":false},{"id":1106282,"name":"Jiaqian Liang","orcid":null,"position":5,"is_corresponding":false},{"id":1106283,"name":"Xinghua Liao","orcid":null,"position":6,"is_corresponding":false},{"id":1105793,"name":"Xiaming Liu","orcid":"0000-0002-1194-8791","position":7,"is_corresponding":false},{"id":1106284,"name":"Yanfei Gao","orcid":null,"position":8,"is_corresponding":false},{"id":1106285,"name":"Xiaoqiang Liu","orcid":null,"position":9,"is_corresponding":false},{"id":1035892,"name":"Keshan Wang","orcid":"0000-0002-4128-2214","position":10,"is_corresponding":false},{"id":1105794,"name":"Bin Fu","orcid":"0000-0001-6686-7561","position":11,"is_corresponding":false},{"id":645041,"name":"Shaoyong Chen","orcid":"0000-0003-0809-8383","position":12,"is_corresponding":false},{"id":1105790,"name":"Ju Guo","orcid":"0000-0002-3413-2234","position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":null,"created_at":"2026-07-19T01:13:30.556819Z","pmid":"37828515","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":[]}