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ResearchIn-Press PreviewCell biology Open Access | 10.1172/jci.insight.185952

ASCL1 regulates and cooperates with FOXA2 to drive terminal neuroendocrine phenotype in prostate cancer

Shaghayegh Nouruzi,1 Takeshi Namekawa,1 Nakisa Tabrizian,1 Maxim Kobelev,1 Olena Sivak,1 Joshua M. Scurll,1 Cassandra Jingjing Cui,1 Dwaipayan Ganguli,2 and Amina Zoubeidi1

1Department of Urologic Sciences, University of British Columbia, Vancouver, Canada

2Vancouver Prostate Centre, Vancouver, Canada

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1Department of Urologic Sciences, University of British Columbia, Vancouver, Canada

2Vancouver Prostate Centre, Vancouver, Canada

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1Department of Urologic Sciences, University of British Columbia, Vancouver, Canada

2Vancouver Prostate Centre, Vancouver, Canada

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1Department of Urologic Sciences, University of British Columbia, Vancouver, Canada

2Vancouver Prostate Centre, Vancouver, Canada

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1Department of Urologic Sciences, University of British Columbia, Vancouver, Canada

2Vancouver Prostate Centre, Vancouver, Canada

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1Department of Urologic Sciences, University of British Columbia, Vancouver, Canada

2Vancouver Prostate Centre, Vancouver, Canada

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1Department of Urologic Sciences, University of British Columbia, Vancouver, Canada

2Vancouver Prostate Centre, Vancouver, Canada

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1Department of Urologic Sciences, University of British Columbia, Vancouver, Canada

2Vancouver Prostate Centre, Vancouver, Canada

Find articles by Ganguli, D. in: JCI | PubMed | Google Scholar

1Department of Urologic Sciences, University of British Columbia, Vancouver, Canada

2Vancouver Prostate Centre, Vancouver, Canada

Find articles by Zoubeidi, A. in: JCI | PubMed | Google Scholar

Published October 29, 2024 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.185952.
Copyright © 2024, Nouruzi et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 29, 2024 - Version history
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Abstract

Lineage plasticity mediates resistance to androgen receptor pathway inhibitors (ARPIs) and progression from adenocarcinoma to neuroendocrine prostate cancer (NEPC), a highly aggressive and poorly understood subtype. ASCL1 has emerged as a central regulator of the lineage plasticity driving neuroendocrine differentiation. Here, we showed that ASCL1 was reprogrammed in ARPI-induced transition to the terminal NEPC and identified that the ASCL1 binding pattern tailored the expression of lineage-determinant transcription factor combinations that underlying discrete terminal NEPC identity. Notably, we identified FOXA2 as a major co-factor of ASCL1 in terminal NEPC, which is highly expressed in ASCL1-driven NEPC. Mechanistically, FOXA2 and ASCL1 interacted and worked in concert to orchestrate terminal neuronal differentiation. We identified that Prospero-Related Homeobox 1 was a target of ASCL1 and FOXA2. Targeting prospero-related homeobox 1 abrogated neuroendocrine characteristics and led to a decrease in cell proliferation in vitro and tumor growth in vivo. Our findings provide insights into the molecular conduit underlying the interplay between different lineage-determinant transcription factors to support the neuroendocrine identity and nominate prospero-related homeobox 1 as a potential target in ASCL1 high NEPC.

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