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Chromatin Accessibility and Pioneer Factor FOXA1 Shape Glucocorticoid Receptor Action in Prostate Cancer

View ORCID ProfileLaura Helminen, Jasmin Huttunen, View ORCID ProfileNiina Aaltonen, View ORCID ProfileEinari A. Niskanen, View ORCID ProfileJorma J. Palvimo, View ORCID ProfileVille Paakinaho
doi: https://doi.org/10.1101/2023.03.03.530941
Laura Helminen
1Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
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Jasmin Huttunen
1Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
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Niina Aaltonen
1Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
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Einari A. Niskanen
1Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
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Jorma J. Palvimo
1Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
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Ville Paakinaho
1Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
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  • For correspondence: ville.paakinaho@uef.fi
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ABSTRACT

Treatment of prostate cancer relies predominantly on the inhibition of androgen receptor (AR) signaling. Despite the initial effectiveness of the antiandrogen therapies, the cancer often develops resistance to the AR blockade. One mechanism of the resistance is glucocorticoid receptor (GR)-mediated replacement of AR function. Nevertheless, the mechanistic ways and means how the GR-mediated antiandrogen resistance occurs have remained elusive. Here, we have discovered several crucial features of GR action in prostate cancer cells through genome-wide techniques. We detected that the replacement of AR by GR in enzalutamide-exposed prostate cancer cells occurs almost exclusively at pre-accessible chromatin sites displaying FOXA1 occupancy. Counterintuitively to the classical pioneer factor model, silencing of FOXA1 potentiated the chromatin binding and transcriptional activity of GR. This was attributed to FOXA1-mediated repression of the NR3C1 (gene encoding GR) expression via the corepressor TLE3. Moreover, the small-molecule inhibition of coactivator p300’s enzymatic activity efficiently restricted GR-mediated gene regulation and cell proliferation. Overall, we identified chromatin pre-accessibility and FOXA1-mediated repression as important regulators of GR action in prostate cancer, pointing out new avenues to oppose steroid receptor-mediated antiandrogen resistance.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted March 03, 2023.
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Chromatin Accessibility and Pioneer Factor FOXA1 Shape Glucocorticoid Receptor Action in Prostate Cancer
Laura Helminen, Jasmin Huttunen, Niina Aaltonen, Einari A. Niskanen, Jorma J. Palvimo, Ville Paakinaho
bioRxiv 2023.03.03.530941; doi: https://doi.org/10.1101/2023.03.03.530941
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Chromatin Accessibility and Pioneer Factor FOXA1 Shape Glucocorticoid Receptor Action in Prostate Cancer
Laura Helminen, Jasmin Huttunen, Niina Aaltonen, Einari A. Niskanen, Jorma J. Palvimo, Ville Paakinaho
bioRxiv 2023.03.03.530941; doi: https://doi.org/10.1101/2023.03.03.530941

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