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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.

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