{"doi":"10.1016/j.celrep.2024.114431","title":"Elevating PLK1 overcomes BETi resistance in prostate cancer via triggering BRD4 phosphorylation-dependent degradation in mitosis","abstract":"Bromodomain-containing protein 4 (BRD4) has emerged as a promising therapeutic target in prostate cancer (PCa). Understanding the mechanisms of BRD4 stability could enhance the clinical response to BRD4-targeted therapy. In this study, we report that BRD4 protein levels are significantly decreased during mitosis in a PLK1-dependent manner. Mechanistically, we show that BRD4 is primarily phosphorylated at T1186 by the CDK1/cyclin B complex, recruiting PLK1 to phosphorylate BRD4 at S24/S1100, which are recognized by the APC/C Cdh1 complex for proteasome pathway degradation. We find that PLK1 overexpression lowers SPOP mutation-stabilized BRD4, consequently rendering PCa cells re-sensitized to BRD4 inhibitors. Intriguingly, we report that sequential treatment of docetaxel and JQ1 resulted in significant inhibition of PCa. Collectively, the results support that PLK1-phosphorylated BRD4 triggers its degradation at M phase. Sequential treatment of docetaxel and JQ1 overcomes BRD4 accumulation-associated bromodomain and extra-terminal inhibitor (BETi) resistance, which may shed light on the development of strategies to treat PCa.","journal":"Cell Reports","year":2024,"id":432346,"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":15,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.952,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":817996,"name":"Ka-wing Fong","orcid":"0000-0001-6995-0264","position":1,"is_corresponding":false},{"id":411939,"name":"Fengyi Mao","orcid":"0000-0001-7785-6606","position":3,"is_corresponding":false},{"id":497890,"name":"Ruixin Wang","orcid":"0000-0002-9615-7541","position":4,"is_corresponding":false},{"id":567667,"name":"Derek B. Allison","orcid":"0000-0002-5119-2474","position":5,"is_corresponding":false},{"id":484016,"name":"Dana Napier","orcid":null,"position":6,"is_corresponding":false},{"id":271896,"name":"Daheng He","orcid":"0000-0003-0399-2466","position":7,"is_corresponding":false},{"id":369266,"name":"Jinpeng Liu","orcid":"0000-0003-4100-0237","position":8,"is_corresponding":false},{"id":567204,"name":"Jing Chen","orcid":"0000-0002-6284-2858","position":9,"is_corresponding":false},{"id":411938,"name":"Yifan Kong","orcid":"0000-0002-5650-8079","position":10,"is_corresponding":false},{"id":411941,"name":"Jinghui Liu","orcid":"0000-0002-9676-1538","position":13,"is_corresponding":false},{"id":497889,"name":"Zhiguo Li","orcid":"0000-0002-6869-2766","position":14,"is_corresponding":false},{"id":351084,"name":"Haining Zhu","orcid":"0000-0001-5498-6694","position":15,"is_corresponding":false},{"id":1447,"name":"Chi Wang","orcid":"0000-0001-8984-4995","position":16,"is_corresponding":false},{"id":411943,"name":"Xiaoqi Liu","orcid":"0000-0002-6613-1746","position":17,"is_corresponding":false},{"id":411940,"name":"Yanquan Zhang","orcid":"0000-0003-3527-9972","position":0,"is_corresponding":true}],"reference_count":84,"raw_metadata":null,"created_at":"2026-07-19T01:59:35.267142Z","pmid":"38968071","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":[]}