The dynamic role of the androgen receptor (AR) and ABL interactor-1 (ABI1) axis in prostate cancer

Abstract

The nuclear hormone receptor and transcription factor, the androgen receptor (AR), is the main driver of prostate cancer growth and disease progression. Hallmark target genes of AR are used as biomarkers to indicate disease progression and treatment response. Furthermore, current clinical treatments for prostate cancer include androgen deprivation treatment and anti-AR which deplete ligand availability or directly target the androgen receptor, respectively. Transcription regulates key functions of living organisms in normal and diseases states, including cell growth and development, embryonic and adult tissue organization, and tumor progression. Here we identify a novel mechanism of transcriptional regulation by an actin regulatory and signaling protein, ABI1. As established by ChIP sequencing and DNA binding assays, ABI1 binds to chromatin through its intrinsically disordered DNA binding domain. Furthermore, ABI1 interacts with AR in vitro and in vivo and targets its activity to specific subset of genes. ABI1-AR driven transcription is dysregulated during prostate tumor progression. Additionally, anti-androgen and anti-AR treatments induce alterations in AR-mediated transcription which leads to downregulation of ABI1 expression and induces disruption of epithelial integrity. The results from this study indicate that ABI1 controls tumor plasticity through connecting actin cytoskeleton and cellular signaling to transcriptional regulation. We propose that ABI1 is a regulator of transcriptional homeostasis in prostate cancer.