Pioneer of prostate cancer: past, present and the future of FOXA1

Abstract

Prostate cancer is the most commonly diagnosed non-cutaneous cancers in North American men. While androgen deprivation has remained as the cornerstone of prostate cancer treatment, resistance ensues leading to lethal disease. Forkhead box A1 (FOXA1) encodes a pioneer factor that induces open chromatin conformation to allow the binding of other transcription factors. Through direct interactions with the Androgen Receptor (AR), FOXA1 helps to shape AR signaling that drives the growth and survival of normal prostate and prostate cancer cells. FOXA1 also possesses an AR-independent role of regulating epithelial-to-mesenchymal transition (EMT). In prostate cancer, mutations converge onto the coding sequence and cis-regulatory elements (CREs) of FOXA1, leading to functional alterations. In addition, FOXA1 activity in prostate cancer can be modulated post-translationally through various mechanisms such as LSD1-mediated protein demethylation. In this review, we describe the latest discoveries related to the function and regulation of FOXA1 in prostate cancer, pointing to their relevance to guide future clinical interventions.

Keywords: FOXA1; epigenetics; pioneer factor; prostate cancer; transcription factor.

Figure 1

Schematic of FOXA1 activity in (A) normal prostate and (B) prostate cancer. (A) FOXA1 preferentially binds to genomic Forkhead motifs marked by H3K4me1/me2 histone modifications. It induces open chromatin conformation and allows for the sequential binding of AR to drive AR transcriptional programs. FOXA1 also inhibits EMT independent of AR. (B) In prostate cancer, FOXA1 can extensively reprogram AR cistrome along with HOXB13. FOXA1 mutations can result in stronger AR binding and significantly alter AR transcriptional programs. FOXA1 mutants can also induce EMT programs to drive cancer metastasis. Abbreviations: ARE, androgen-receptor response element; EMT, epithelial-mesenchymal transition

Figure 2

Protein map of FOXA1 functional domains and secondary structures. Residues in red represent Wing2 mutational hotspot. FOXA1 methylation site at lysine 270 (K270) is highlighted. Abbreviation: TA, transactivation domain

Figure 3

Noncoding mutations converge onto FOXA1. FOXA1 locus is frequently altered by structural rearrangements inclusive of translocations and tandem duplications. Translocations can result in genes hijacking the activity of the FOXMIND enhancer. In addition, translocations can insert oncogenes upstream of FOXA1. Along with FOXMIND, 5 additional functional CREs harbouring SNVs are identified near FOXA1 locus which can affect the expression of FOXA1. The 3′ UTR region of FOXA1 is frequently mutated with indels being the dominant type of mutation. Abbreviations: SNV, single nucleotide variant; 3′ UTR, 3′ untranslated region; CRE, cis-regulatory elements