ASCL1 activates neuronal stem cell-like lineage programming through remodeling of the chromatin landscape in prostate cancer.

Autor: Nouruzi S; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V5Z 1M9, Canada.; Vancouver Prostate Centre, Vancouver, BC, V6H 3Z6, Canada., Ganguli D; Vancouver Prostate Centre, Vancouver, BC, V6H 3Z6, Canada., Tabrizian N; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V5Z 1M9, Canada.; Vancouver Prostate Centre, Vancouver, BC, V6H 3Z6, Canada., Kobelev M; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V5Z 1M9, Canada.; Vancouver Prostate Centre, Vancouver, BC, V6H 3Z6, Canada., Sivak O; Vancouver Prostate Centre, Vancouver, BC, V6H 3Z6, Canada., Namekawa T; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V5Z 1M9, Canada.; Vancouver Prostate Centre, Vancouver, BC, V6H 3Z6, Canada., Thaper D; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V5Z 1M9, Canada.; Vancouver Prostate Centre, Vancouver, BC, V6H 3Z6, Canada., Baca SC; Departement of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States., Freedman ML; Departement of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States., Aguda A; Vancouver Prostate Centre, Vancouver, BC, V6H 3Z6, Canada., Davies A; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V5Z 1M9, Canada.; Vancouver Prostate Centre, Vancouver, BC, V6H 3Z6, Canada., Zoubeidi A; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V5Z 1M9, Canada. azoubeidi@prostatecentre.com.; Vancouver Prostate Centre, Vancouver, BC, V6H 3Z6, Canada. azoubeidi@prostatecentre.com.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Apr 27; Vol. 13 (1), pp. 2282. Date of Electronic Publication: 2022 Apr 27.
DOI: 10.1038/s41467-022-29963-5
Abstrakt: Treatment with androgen receptor pathway inhibitors (ARPIs) in prostate cancer leads to the emergence of resistant tumors characterized by lineage plasticity and differentiation toward neuroendocrine lineage. Here, we find that ARPIs induce a rapid epigenetic alteration mediated by large-scale chromatin remodeling to support activation of stem/neuronal transcriptional programs. We identify the proneuronal transcription factor ASCL1 motif to be enriched in hyper-accessible regions. ASCL1 acts as a driver of the lineage plastic, neuronal transcriptional program to support treatment resistance and neuroendocrine phenotype. Targeting ASCL1 switches the neuroendocrine lineage back to the luminal epithelial state. This effect is modulated by disruption of the polycomb repressive complex-2 through UHRF1/AMPK axis and change the chromatin architecture in favor of luminal phenotype. Our study provides insights into the epigenetic alterations induced by ARPIs, governed by ASCL1, provides a proof of principle of targeting ASCL1 to reverse neuroendocrine phenotype, support luminal conversion and re-addiction to ARPIs.
(© 2022. The Author(s).)
Databáze: MEDLINE
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