{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T01:27:30Z","timestamp":1786670850746,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,13]]},"group-title":"Cancer Biology","reference-count":0,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Heart, Lung and Blood Institute","award":["PO1 HL146372"],"award-info":[{"award-number":["PO1 HL146372"]}]},{"name":"National Cancer Institute","award":["P30 CA043703"],"award-info":[{"award-number":["P30 CA043703"]}]},{"name":"National Cancer Institute","award":["RO1 CA204373"],"award-info":[{"award-number":["RO1 CA204373"]}]},{"name":"National Cancer Institute","award":["R21 CA263430"],"award-info":[{"award-number":["R21 CA263430"]}]},{"name":"NIH Shared Instrument award","award":["S10OD018205"],"award-info":[{"award-number":["S10OD018205"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,13]]},"abstract":"<jats:p>Urothelial cancer (UC) cells of the luminal subtype exhibit partial, incomplete differentiation towards umbrella cells that line bladder lumen, seen by morphology and gene expression. Differentiation is stalled even though the cells express master transcription factors (MTFs) that drive luminal urothelial differentiation, e.g., FOXA1 and CEBPB, at levels seen in normal differentiated urothelium. We therefore analyzed the FOXA1\/CEBPB MTF hub by mass spectrometry. SWI\/SNF coactivator complex (CoA) components, e.g., SMARCA4, ARID1A, that read the epigenetic activation mark histone 3 lysine 27 acetylation (H3K27ac) and use ATP-hydrolysis to open chromatin, were the most abundant proteins pulled-down with FOXA1\/CEBPB. However, genes for these and other CoA, e.g., CREBBP, EP300 that write H3K27ac, were mutated\/deleted in &gt;95% of UCs in clinical series. Also contained in the hub were corepressors (CoR) that erase H3K27ac and close chromatin, e.g., HDAC1, CHD4; genes for these CoR were recurrently gained in UCs. Chromatin analyses showed H3K27ac-centered remodeling was needed to activate umbrella but not constitutively accessible cell growth\/division\/housekeeping genes. Restoring ARID1A into ARID1A-mutated UC cells using lentiviral transduction, or inhibiting CoR with siRNA or small molecules, activated umbrella genes and terminated replications. In summary, UC-genesis selects for loss- and gain-of-function of CoA and CoR respectively in the urothelial-lineage MTF hub; small molecule CoR-inhibitors are candidate remedies to renew maturation towards terminal differentiated-fates.<\/jats:p>","DOI":"10.64898\/2026.08.12.744501","type":"posted-content","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:50:16Z","timestamp":1786668616000},"source":"Crossref","is-referenced-by-count":0,"title":["Urothelial-lineage master transcription factor hub proteomics shows mechanisms impeding urothelial cancer cell differentiation"],"prefix":"10.64898","author":[{"given":"Caroline","family":"Schuerger","sequence":"first","affiliation":[{"name":"Cleveland Clinic;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudipta","family":"Biswas","sequence":"additional","affiliation":[{"name":"Cleveland Clinic;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwok Peng","family":"Ng","sequence":"additional","affiliation":[{"name":"Cleveland Clinic;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Cardone","sequence":"additional","affiliation":[{"name":"Cleveland Clinic;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaorong","family":"Gu","sequence":"additional","affiliation":[{"name":"Cleveland Clinic;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinjini","family":"Ganguly","sequence":"additional","affiliation":[{"name":"Cleveland Clinic;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Tohme","sequence":"additional","affiliation":[{"name":"Cleveland Clinic;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arda","family":"Durmaz","sequence":"additional","affiliation":[{"name":"Cleveland Clinic;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Stich","sequence":"additional","affiliation":[{"name":"Heidelberg University;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J.","family":"Lindner","sequence":"additional","affiliation":[{"name":"Cleveland Clinic;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Babal","family":"Jha","sequence":"additional","affiliation":[{"name":"Cleveland Clinic;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar Y.","family":"Mian","sequence":"additional","affiliation":[{"name":"Fred Hutch Cancer Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yogen","family":"Saunthararajah","sequence":"additional","affiliation":[{"name":"Cleveland Clinic;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.08.12.744501","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:50:16Z","timestamp":1786668616000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.08.12.744501"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,13]]},"references-count":0,"URL":"https:\/\/doi.org\/10.64898\/2026.08.12.744501","relation":{},"subject":[],"published":{"date-parts":[[2026,8,13]]},"subtype":"preprint"}}