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

Shaghayegh Nouruzi, Dwaipayan Ganguli, Nakisa Tabrizian, Maxim Kobelev, Olena Sivak, Takeshi Namekawa, Daksh Thaper, Sylvan C. Baca, Matthew L. Freedman, Adeleke Aguda, Alastair Davies and Amina Zoubeidi ()
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Shaghayegh Nouruzi: University of British Columbia
Dwaipayan Ganguli: Vancouver Prostate Centre
Nakisa Tabrizian: University of British Columbia
Maxim Kobelev: University of British Columbia
Olena Sivak: Vancouver Prostate Centre
Takeshi Namekawa: University of British Columbia
Daksh Thaper: University of British Columbia
Sylvan C. Baca: Dana-Farber Cancer Institute
Matthew L. Freedman: Dana-Farber Cancer Institute
Adeleke Aguda: Vancouver Prostate Centre
Alastair Davies: University of British Columbia
Amina Zoubeidi: University of British Columbia

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-29963-5

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