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hASH1 nuclear localization persists in neuroendocrine transdifferentiated prostate cancer cells, even upon reintroduction of androgen

Fraser, Jennifer A.; Sutton, Joseph E.; Tazayoni, Saba; Bruce, Isla; Poole, Amy V.


Jennifer A. Fraser

Joseph E. Sutton

Saba Tazayoni

Isla Bruce


Neuroendocrine prostate cancer (NEPC) is thought to arise as prostate adenocarcinoma cells transdifferentiate into neuroendocrine (NE) cells to escape potent anti-androgen therapies however, the exact molecular events accompanying NE transdifferentiation and
their plasticity remain poorly defined. Cell fate regulator ASCL1/hASH1’s expression was markedly induced in androgen deprived (AD) LNCaP cells and prominent nuclear localisation accompanied acquisition of the NE-like morphology and expression
of NE markers (NSE). By contrast, androgen-insensitive PC3 and DU145 cells displayed clear nuclear hASH1 localisation under control conditions that was unchanged by AD, suggesting AR signalling negatively regulated hASH1 expression and localisation. Synthetic androgen (R1881) prevented NE transdifferentiation of AD LNCaP cells and markedly suppressed expression of key regulators of lineage commitment and neurogenesis (REST and ASCL1/hASH1). Post-AD, NE LNCaP cells rapidly lost NE-like morphology following R1881 treatment, yet ASCL1/hASH1 expression was resistant to R1881 treatment and hASH1 nuclear localisation remained evident in apparently dedifferentiated LNCaP cells. Consequently, NE cells may not fully revert to an epithelial state and retain key NE-like features, suggesting a “hybrid” phenotype. This could fuel greater NE transdifferentiation, therapeutic resistance and NEPC evolution upon subsequent androgen deprivation. Such knowledge could facilitate CRPC tumour stratification and identify targets for more effective NEPC management.


Fraser, J. A., Sutton, J. E., Tazayoni, S., Bruce, I., & Poole, A. V. (2019). hASH1 nuclear localization persists in neuroendocrine transdifferentiated prostate cancer cells, even upon reintroduction of androgen. Scientific Reports, 9,

Journal Article Type Article
Acceptance Date Nov 27, 2019
Online Publication Date Dec 13, 2019
Publication Date Dec 13, 2019
Deposit Date Dec 17, 2019
Publicly Available Date Dec 17, 2019
Journal Scientific Reports
Electronic ISSN 2045-2322
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 9
Article Number 19076 (2019)
Keywords neuroendocrine prostate cancer; neuroendocrine transdifferentiation; androgen deprivation; ASCL1/hASH1; lineage plasticity; hybrid phenotype
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HASH1 Nuclear Localization Persists In Neuroendocrine Transdifferentiated Prostate Cancer Cells, Even Upon Reintroduction Of Androgen (published version) (5.5 Mb)

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Copyright Statement
This article is licensed under a Creative Commons Attribution 4.0 International License.

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