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

Author

Listed:
  • Shaghayegh Nouruzi

    (University of British Columbia
    Vancouver Prostate Centre)

  • Dwaipayan Ganguli

    (Vancouver Prostate Centre)

  • Nakisa Tabrizian

    (University of British Columbia
    Vancouver Prostate Centre)

  • Maxim Kobelev

    (University of British Columbia
    Vancouver Prostate Centre)

  • Olena Sivak

    (Vancouver Prostate Centre)

  • Takeshi Namekawa

    (University of British Columbia
    Vancouver Prostate Centre)

  • Daksh Thaper

    (University of British Columbia
    Vancouver Prostate Centre)

  • 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
    Vancouver Prostate Centre)

  • Amina Zoubeidi

    (University of British Columbia
    Vancouver Prostate Centre)

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.

Suggested Citation

  • Shaghayegh Nouruzi & Dwaipayan Ganguli & Nakisa Tabrizian & Maxim Kobelev & Olena Sivak & Takeshi Namekawa & Daksh Thaper & Sylvan C. Baca & Matthew L. Freedman & Adeleke Aguda & Alastair Davies & Ami, 2022. "ASCL1 activates neuronal stem cell-like lineage programming through remodeling of the chromatin landscape in prostate cancer," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29963-5
    DOI: 10.1038/s41467-022-29963-5
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    References listed on IDEAS

    as
    1. Xi Chen & Ricardo J. Miragaia & Kedar Nath Natarajan & Sarah A. Teichmann, 2018. "A rapid and robust method for single cell chromatin accessibility profiling," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
    2. Paloma Cejas & Yingtian Xie & Alba Font-Tello & Klothilda Lim & Sudeepa Syamala & Xintao Qiu & Alok K. Tewari & Neel Shah & Holly M. Nguyen & Radhika A. Patel & Lisha Brown & Ilsa Coleman & Wenzel M. , 2021. "Subtype heterogeneity and epigenetic convergence in neuroendocrine prostate cancer," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    3. Nicholas J. Brady & Alyssa M. Bagadion & Richa Singh & Vincenza Conteduca & Lucie Van Emmenis & Elisa Arceci & Hubert Pakula & Ryan Carelli & Francesca Khani & Martin Bakht & Michael Sigouros & Rohan , 2021. "Temporal evolution of cellular heterogeneity during the progression to advanced AR-negative prostate cancer," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
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    Cited by:

    1. Goutam Chakraborty & Kasmira Gupta & Natasha Kyprianou, 2023. "Epigenetic mechanisms underlying subtype heterogeneity and tumor recurrence in prostate cancer," Nature Communications, Nature, vol. 14(1), pages 1-4, December.

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