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

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, Hwa Young Yun, Julie Livingstone, Vincent Huang, Takafumi N. Yamaguchi, Shadrielle M. G. Espiritu, Yanyun Zhu, Tesa M. Severson, Alex Murison, Sarina Cameron, Wilbert Zwart, Theodorus Kwast, Trevor J. Pugh, Michael Fraser, Paul C. Boutros, Robert G. Bristow, Housheng Hansen He and Mathieu Lupien ()
Additional contact information
Stanley Zhou: University Health Network
James R. Hawley: University Health Network
Fraser Soares: University Health Network
Giacomo Grillo: University Health Network
Mona Teng: University Health Network
Seyed Ali Madani Tonekaboni: University Health Network
Junjie Tony Hua: University Health Network
Ken J. Kron: University Health Network
Parisa Mazrooei: University Health Network
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
Theodorus Kwast: University of Toronto
Trevor J. Pugh: University Health Network
Michael Fraser: Ontario Institute for Cancer Research
Paul C. Boutros: University of Toronto
Robert G. Bristow: University Health Network
Housheng Hansen He: University Health Network
Mathieu Lupien: University Health Network

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14318-9

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