{"doi":"10.1073/pnas.2411321121","title":"Functional inversion of circadian regulator REV-ERBα leads to tumorigenic gene reprogramming","abstract":"Profound functional switch of key regulatory factors may play a major role in homeostasis and disease. Dysregulation of circadian rhythm (CR) is strongly implicated in cancer with mechanisms poorly understood. We report here that the function of REV-ERBα, a major CR regulator of the orphan nuclear receptor subfamily, is dramatically altered in tumors in both its genome binding and functional mode. Loss of CR is linked to a functional inversion of REV-ERBα from a repressor in control of CR and metabolic gene programs in normal tissues to a strong activator in different cancers. Through changing its association from NCoR/HDAC3 corepressor complex to BRD4/p300 coactivators, REV-ERBα directly activates thousands of genes including tumorigenic programs such as MAPK and PI3K-Akt signaling. Functioning as a master transcriptional activator, REV-ERBα partners with pioneer factor FOXA1 and directly stimulates a large number of signaling genes, including multiple growth factors, receptor tyrosine kinases, RASs, AKTs, and MAPKs. Moreover, elevated REV-ERBα reprograms FOXA1 to bind new targets through a BRD4-mediated increase in local chromatin accessibility. Pharmacological targeting with SR8278 diminishes the function of both REV-ERBα and FOXA1 and synergizes with BRD4 inhibitor in effective suppression of tumorigenic programs and tumor growth. Thus, our study revealed a functional inversion by a CR regulator in driving gene reprogramming as an unexpected paradigm of tumorigenesis mechanism and demonstrated a high effectiveness of therapeutic targeting such switch.","journal":"Proceedings of the National Academy of Sciences","year":2024,"id":435799,"datarank":0.38474240361923057,"base_score":2.5649493574615367,"endowment":2.5649493574615367,"self_citation_contribution":0.38474240361923057,"citation_network_contribution":0.0,"self_endowment_contribution":0.38474240361923057,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9585,"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":1243404,"name":"Xiong Zhang","orcid":"0000-0002-5970-4614","position":1,"is_corresponding":false},{"id":871337,"name":"Demin Cai","orcid":"0000-0003-0500-5292","position":2,"is_corresponding":false},{"id":1243923,"name":"Xingling Zheng","orcid":null,"position":3,"is_corresponding":false},{"id":361697,"name":"Xuan Zhao","orcid":"0009-0005-1437-5764","position":4,"is_corresponding":false},{"id":490490,"name":"June X. Zou","orcid":"0000-0003-1457-3187","position":5,"is_corresponding":false},{"id":323532,"name":"Jin Zhang","orcid":"0000-0002-6835-920X","position":6,"is_corresponding":false},{"id":356145,"name":"Alexander D. Borowsky","orcid":"0000-0003-3117-9202","position":7,"is_corresponding":false},{"id":642437,"name":"Marc Dall’Era","orcid":"0000-0002-2301-2683","position":8,"is_corresponding":false},{"id":291421,"name":"Eva Corey","orcid":"0000-0002-9244-3807","position":9,"is_corresponding":false},{"id":634910,"name":"Nicholas Mitsiades","orcid":"0000-0002-4659-476X","position":10,"is_corresponding":false},{"id":1243405,"name":"Hsing‐Jien Kung","orcid":"0000-0002-9903-5830","position":11,"is_corresponding":false},{"id":341962,"name":"Xinbin Chen","orcid":"0000-0002-4582-6506","position":12,"is_corresponding":false},{"id":237445,"name":"Jian Jian Li","orcid":"0000-0003-3694-9675","position":13,"is_corresponding":false},{"id":80487,"name":"Michael Downes","orcid":"0000-0002-6351-9585","position":14,"is_corresponding":false},{"id":80488,"name":"Ronald M. Evans","orcid":"0000-0002-9986-5965","position":15,"is_corresponding":false},{"id":261267,"name":"Hong-Wu Chen","orcid":null,"position":16,"is_corresponding":false},{"id":924258,"name":"Yatian Yang","orcid":null,"position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:00:08.103086Z","pmid":"39383000","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":[]}