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Article

Zeb1 and SK3 Channel Are Up-Regulated in Castration-Resistant Prostate Cancer and Promote Neuroendocrine Differentiation

1
N2C UMR 1069, University of Tours, INSERM, F-37032 Tours, France
2
Department of Oncology, CHRU Bretonneau, CEDEX 9, F-37044 Tours, France
3
CHRU of Tours, Department of Pathology, N2C UMR 1069, University of Tours, INSERM, CEDEX 9, F-37044 Tours, France
4
CHRU of Tours, Department of Urology, CEDEX 9, F-37044 Tours, France
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Angie Rizzino
Cancers 2021, 13(12), 2947; https://doi.org/10.3390/cancers13122947
Received: 3 May 2021 / Revised: 1 June 2021 / Accepted: 9 June 2021 / Published: 12 June 2021
Currently, neuroendocrine prostate cancers remain fatal, so it is crucial to better understand mechanisms of resistance to hormone therapy driving this phenotype. We have shown that Enza, a new generation hormone therapy, promotes prostate cancer cells neurodifferentiation by activating a positive feedback loop between the key transcription factor of epithelial to mesenchymal transition Zeb1 and the calcium-sensitive potassium channel SK3. These two actors are overexpressed in patients with neuroendocrine castration-resistant prostate cancer. Targeting SK3 channel by Ohmline, a synthetic ether lipid, inhibits neuroendocrine differentiation of prostate cancer cells, which opens new therapeutic prospects for neuroendocrine prostate cancers.
Therapeutic strategies for metastatic castration-resistant prostate cancer aim to target androgen receptor signaling. Despite initial survival benefits, treatment resistance invariably occurs, leading to lethal disease. Therapies targeting the androgen receptor can induce the emergence of a neuroendocrine phenotype and reactivate embryonic programs associated with epithelial to mesenchymal transition. We recently reported that dysregulation of the calcium signal can induce the transcription factor Zeb1, a key determinant of cell plasticity during tumor progression. The aim of this study was to determine whether the androgen receptor-targeted treatment Enzalutamide could induce dysregulation of the calcium signal involved in the progression toward epithelial to mesenchymal transition and neuroendocrine differentiation, contributing to therapeutic escape. Our results show that Zeb1 and the SK3 potassium channel are overexpressed in vivo in neuroendocrine castration-resistant prostate cancer and in vitro in LNCaP cells neurodifferentiated after Enzalutamide treatment. Moreover, the neuroendocrine phenotype is associated with a deregulation of the expression of Orai calcium channels. We showed that Zeb1 and SK3 are critical drivers of neuroendocrine differentiation. Interestingly, Ohmline, an SK3 inhibitor, can prevent the expression of Zeb1 and neuroendocrine markers induced by Enzalutamide. This study offers new perspectives to increase hormone therapy efficacy and improve clinical outcomes. View Full-Text
Keywords: prostate cancer; neuroendocrine differenciation; epithelial to mesenchymal transition; calcium signaling prostate cancer; neuroendocrine differenciation; epithelial to mesenchymal transition; calcium signaling
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MDPI and ACS Style

Bery, F.; Cancel, M.; Guéguinou, M.; Potier-Cartereau, M.; Vandier, C.; Chantôme, A.; Guibon, R.; Bruyère, F.; Fromont, G.; Mahéo, K. Zeb1 and SK3 Channel Are Up-Regulated in Castration-Resistant Prostate Cancer and Promote Neuroendocrine Differentiation. Cancers 2021, 13, 2947. https://doi.org/10.3390/cancers13122947

AMA Style

Bery F, Cancel M, Guéguinou M, Potier-Cartereau M, Vandier C, Chantôme A, Guibon R, Bruyère F, Fromont G, Mahéo K. Zeb1 and SK3 Channel Are Up-Regulated in Castration-Resistant Prostate Cancer and Promote Neuroendocrine Differentiation. Cancers. 2021; 13(12):2947. https://doi.org/10.3390/cancers13122947

Chicago/Turabian Style

Bery, Fanny, Mathilde Cancel, Maxime Guéguinou, Marie Potier-Cartereau, Christophe Vandier, Aurélie Chantôme, Roseline Guibon, Franck Bruyère, Gaëlle Fromont, and Karine Mahéo. 2021. "Zeb1 and SK3 Channel Are Up-Regulated in Castration-Resistant Prostate Cancer and Promote Neuroendocrine Differentiation" Cancers 13, no. 12: 2947. https://doi.org/10.3390/cancers13122947

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