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

Autor:	Nouruzi S; Department of Urologic Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.; Vancouver Prostate Centre, Vancouver, British Columbia, Canada., Namekawa T; Department of Urologic Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.; Vancouver Prostate Centre, Vancouver, British Columbia, Canada., Tabrizian N; Department of Urologic Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.; Vancouver Prostate Centre, Vancouver, British Columbia, Canada., Kobelev M; Department of Urologic Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.; Vancouver Prostate Centre, Vancouver, British Columbia, Canada., Sivak O; Vancouver Prostate Centre, Vancouver, British Columbia, Canada., Scurll JM; Department of Urologic Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.; Vancouver Prostate Centre, Vancouver, British Columbia, Canada., Cui CJ; Department of Urologic Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.; Vancouver Prostate Centre, Vancouver, British Columbia, Canada., Ganguli D; Vancouver Prostate Centre, Vancouver, British Columbia, Canada., Zoubeidi A; Department of Urologic Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.; Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2024 Dec 06; Vol. 9 (23). Date of Electronic Publication: 2024 Dec 06.
DOI:	10.1172/jci.insight.185952
Abstrakt:	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. Neuronal transcription factor 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 terminal NEPC and identified that the ASCL1 binding pattern tailored the expression of lineage-determinant transcription factor combinations that underlie discrete terminal NEPC identity. Notably, we identified FOXA2 as a major cofactor 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 homeobox 1 was a target of ASCL1 and FOXA2. Targeting prospero 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 homeobox 1 as a potential target in ASCL1-high NEPC.
Databáze:	MEDLINE
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