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Multifactorial ERbeta and NOTCH1 control of squamous differentiation and cancer

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Brooks Y. S., Ostano P., Jo S. H., Dai J., Getsios S., Dziunycz P., Hofbauer G. F., Cerveny K., Chiorino G., Lefort K., Dotto G. P.,
Project Cancer stromal cell genetic control
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Original article (peer-reviewed)

Journal J Clin Invest
Volume (Issue) 124
Page(s) 2260 - 76
Title of proceedings J Clin Invest


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 beta (ERbeta) directly controlling its expression in differentiation. DLX5 and ERG3 are required for RNA polymerase II (PolII) recruitment to the NOTCH1 locus, while ERbeta controls NOTCH1 transcription through RNA PolII pause release. Expression of several identified NOTCH1 regulators, including ERbeta, is frequently compromised in skin, head and neck, and lung SCCs and SCC-derived cell lines. Furthermore, a keratinocyte ERbeta-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 ERbeta expression or treatment with ERbeta 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.