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 CameronWilbert Zwart, Theodorus van der Kwast, Trevor J. Pugh, Michael Fraser, Paul C. Boutros, Robert G. Bristow, Housheng Hansen He, Mathieu Lupien

Research output: Contribution to journalArticleAcademicpeer-review

14 Citations (Scopus)

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.

Original languageEnglish
Article number441
Number of pages13
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - 23 Jan 2020

Keywords

  • Binding Sites
  • Cell Line, Tumor
  • Cell Proliferation/genetics
  • Gene Expression Regulation, Neoplastic
  • Hepatocyte Nuclear Factor 3-alpha/genetics
  • Humans
  • Male
  • Mutation
  • Prostatic Neoplasms/genetics
  • Regulatory Sequences, Nucleic Acid
  • Transcription Factors/metabolism

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