title: Multifactorial ERβ and NOTCH1 control of squamous differentiation and cancer.
abstract: Downmodulation or loss-of-function mutations of the gene encoding NOTCH1 are associated with dysfunctional squamous cell differentiation and development of squamous cell carcinoma (SCC) in skin and internal organs. While NOTCH1 receptor activation has been well characterized, little is known about how NOTCH1 gene transcription is regulated. Using bioinformatics and functional screening approaches, we identified several regulators of the NOTCH1 gene in keratinocytes, with the transcription factors DLX5 and EGR3 and estrogen receptor β (ERβ) directly controlling its expression in differentiation. DLX5 and ERG3 are required for RNA polymerase II (PolII) recruitment to the NOTCH1 locus, while ERβ controls NOTCH1 transcription through RNA PolII pause release. Expression of several identified NOTCH1 regulators, including ERβ, is frequently compromised in skin, head and neck, and lung SCCs and SCC-derived cell lines. Furthermore, a keratinocyte ERβ-dependent program of gene expression is subverted in SCCs from various body sites, and there are consistent differences in mutation and gene-expression signatures of head and neck and lung SCCs in female versus male patients. Experimentally increased ERβ expression or treatment with ERβ agonists inhibited proliferation of SCC cells and promoted NOTCH1 expression and squamous differentiation both in vitro and in mouse xenotransplants. Our data identify a link between transcriptional control of NOTCH1 expression and the estrogen response in keratinocytes, with implications for differentiation therapy of squamous cancer.
authors.forename: Yang Sui
authors.initials: YS
authors.lastname: Brooks
authors.forename: Paola
authors.initials: P
authors.lastname: Ostano
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Jo
authors.forename: Jun
authors.initials: J
authors.lastname: Dai
authors.forename: Spiro
authors.initials: S
authors.lastname: Getsios
authors.forename: Piotr
authors.initials: P
authors.lastname: Dziunycz
authors.forename: Günther F L
authors.initials: GF
authors.lastname: Hofbauer
authors.forename: Kara
authors.initials: K
authors.lastname: Cerveny
authors.forename: Giovanna
authors.initials: G
authors.lastname: Chiorino
authors.forename: Karine
authors.initials: K
authors.lastname: Lefort
authors.forename: G Paolo
authors.initials: GP
authors.lastname: Dotto
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D047629:Estrogen Receptor beta; C497761:NOTCH1 protein, human; D009363:Neoplasm Proteins; D051881:Receptor, Notch1; D012319:RNA Polymerase II
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