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

  • Author(s): Zhou, Stanley
  • Hawley, James R
  • Soares, Fraser
  • Grillo, Giacomo
  • Teng, Mona
  • Madani Tonekaboni, Seyed Ali
  • Hua, Junjie Tony
  • Kron, Ken J
  • Mazrooei, Parisa
  • Ahmed, Musaddeque
  • Arlidge, Christopher
  • Yun, Hwa Young
  • Livingstone, Julie
  • Huang, Vincent
  • Yamaguchi, Takafumi N
  • Espiritu, Shadrielle MG
  • Zhu, Yanyun
  • Severson, Tesa M
  • Murison, Alex
  • Cameron, Sarina
  • Zwart, Wilbert
  • van der Kwast, Theodorus
  • Pugh, Trevor J
  • Fraser, Michael
  • Boutros, Paul C
  • Bristow, Robert G
  • He, Housheng Hansen
  • Lupien, Mathieu
  • et al.

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.

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