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Noncoding mutations target cis-regulatory elements of the FOXA1 plexus in prostate cancer

Author

Listed:
  • Stanley Zhou

    (University Health Network
    University of Toronto)

  • James R. Hawley

    (University Health Network
    University of Toronto)

  • Fraser Soares

    (University Health Network)

  • Giacomo Grillo

    (University Health Network)

  • Mona Teng

    (University Health Network
    University of Toronto)

  • Seyed Ali Madani Tonekaboni

    (University Health Network
    University of Toronto)

  • Junjie Tony Hua

    (University Health Network
    University of Toronto)

  • Ken J. Kron

    (University Health Network)

  • Parisa Mazrooei

    (University Health Network
    University of Toronto)

  • Musaddeque Ahmed

    (University Health Network)

  • Christopher Arlidge

    (University Health Network)

  • Hwa Young Yun

    (University Health Network)

  • Julie Livingstone

    (Ontario Institute for Cancer Research)

  • Vincent Huang

    (Ontario Institute for Cancer Research)

  • Takafumi N. Yamaguchi

    (Ontario Institute for Cancer Research)

  • Shadrielle M. G. Espiritu

    (Ontario Institute for Cancer Research)

  • Yanyun Zhu

    (the Netherlands Cancer Institute)

  • Tesa M. Severson

    (the Netherlands Cancer Institute)

  • Alex Murison

    (University Health Network)

  • Sarina Cameron

    (University Health Network)

  • Wilbert Zwart

    (the Netherlands Cancer Institute
    Eindhoven University of Technology)

  • Theodorus Kwast

    (University of Toronto)

  • Trevor J. Pugh

    (University Health Network
    University of Toronto
    Ontario Institute for Cancer Research)

  • Michael Fraser

    (Ontario Institute for Cancer Research)

  • Paul C. Boutros

    (University of Toronto
    Ontario Institute for Cancer Research
    University of Toronto
    University of California)

  • Robert G. Bristow

    (University Health Network
    University of Toronto
    University of Toronto
    CRUK Manchester Institute and Manchester Cancer Research Centre)

  • Housheng Hansen He

    (University Health Network
    University of Toronto)

  • Mathieu Lupien

    (University Health Network
    University of Toronto
    Ontario Institute for Cancer Research)

Abstract

Prostate cancer is the second most commonly diagnosed malignancy among men worldwide. Recurrently mutated in primary and metastatic prostate tumors, FOXA1 encodes a pioneer transcription factor involved in disease onset and progression through both androgen receptor-dependent and androgen receptor-independent mechanisms. Despite its oncogenic properties however, the regulation of FOXA1 expression remains unknown. Here, we identify a set of six cis-regulatory elements in the FOXA1 regulatory plexus harboring somatic single-nucleotide variants in primary prostate tumors. We find that deletion and repression of these cis-regulatory elements significantly decreases FOXA1 expression and prostate cancer cell growth. Six of the ten single-nucleotide variants mapping to FOXA1 regulatory plexus significantly alter the transactivation potential of cis-regulatory elements by modulating the binding of transcription factors. Collectively, our results identify cis-regulatory elements within the FOXA1 plexus mutated in primary prostate tumors as potential targets for therapeutic intervention.

Suggested Citation

  • Stanley Zhou & James R. Hawley & Fraser Soares & Giacomo Grillo & Mona Teng & Seyed Ali Madani Tonekaboni & Junjie Tony Hua & Ken J. Kron & Parisa Mazrooei & Musaddeque Ahmed & Christopher Arlidge & H, 2020. "Noncoding mutations target cis-regulatory elements of the FOXA1 plexus in prostate cancer," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14318-9
    DOI: 10.1038/s41467-020-14318-9
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    Cited by:

    1. Alexandros Armaos & François Serra & Iker Núñez-Carpintero & Ji-Heui Seo & Sylvan C. Baca & Stefano Gustincich & Alfonso Valencia & Matthew L. Freedman & Davide Cirillo & Claudia Giambartolomei & Gian, 2023. "The PENGUIN approach to reconstruct protein interactions at enhancer-promoter regions and its application to prostate cancer," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Jeroen Kneppers & Tesa M. Severson & Joseph C. Siefert & Pieter Schol & Stacey E. P. Joosten & Ivan Pak Lok Yu & Chia-Chi Flora Huang & Tunç Morova & Umut Berkay Altıntaş & Claudia Giambartolomei & Ji, 2022. "Extensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Roberta Esposito & Andrés Lanzós & Tina Uroda & Sunandini Ramnarayanan & Isabel Büchi & Taisia Polidori & Hugo Guillen-Ramirez & Ante Mihaljevic & Bernard Mefi Merlin & Lia Mela & Eugenio Zoni & Lusin, 2023. "Tumour mutations in long noncoding RNAs enhance cell fitness," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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