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

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.