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.

Abstract

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.

Citation

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, Article 19076 (2019). https://doi.org/10.1038/s41598-019-55665-y

• 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)
• DOI: https://doi.org/10.1038/s41598-019-55665-y
• Keywords: neuroendocrine prostate cancer; neuroendocrine transdifferentiation; androgen deprivation; ASCL1/hASH1; lineage plasticity; hybrid phenotype
• Public URL: http://researchrepository.napier.ac.uk/Output/2366004