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

Stanley Zhou1,2, James R Hawley1,2, Fraser Soares1

  • 1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Nature Communications
|January 25, 2020
PubMed

Insights

Researchers discovered that mutations in regulatory elements controlling FOXA1 (a gene linked to prostate cancer) significantly impact gene expression and cancer cell growth. These findings highlight potential new therapeutic targets for prostate cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Prostate cancer is a leading global malignancy in men.
  • The FOXA1 gene, encoding a pioneer transcription factor, is frequently mutated in prostate tumors and influences disease progression.
  • Mechanisms regulating FOXA1 expression in prostate cancer remain largely unknown.

Purpose of the Study:

  • To identify and characterize cis-regulatory elements controlling FOXA1 expression.
  • To investigate the impact of somatic mutations within these elements on FOXA1 regulation and prostate cancer.
  • To explore the therapeutic potential of targeting FOXA1 regulatory elements.

Main Methods:

  • Identification of cis-regulatory elements in the FOXA1 regulatory plexus.
  • Analysis of somatic single-nucleotide variants in these elements from primary prostate tumors.
  • Functional assays involving deletion and repression of cis-regulatory elements.
  • Assessment of transcription factor binding and transactivation potential alterations.

Main Results:

  • Six cis-regulatory elements within the FOXA1 plexus were identified, harboring somatic mutations in prostate tumors.
  • Deletion or repression of these elements led to decreased FOXA1 expression and reduced prostate cancer cell growth.
  • Six of ten single-nucleotide variants significantly altered the regulatory activity of cis-elements by modulating transcription factor binding.

Conclusions:

  • Mutations in the FOXA1 regulatory plexus are implicated in prostate cancer development.
  • These mutated cis-regulatory elements represent potential therapeutic targets for intervention in prostate cancer.

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