Human-specific genomic evolution of a regulatory network enables fine-tuning of N-cadherin gene expression

Androgen receptor (AR), a member of the nuclear receptor superfamily controls prostate epithelial cell plasticity by repressing a panel of genes involved in epithelial-mesenchymal transition (EMT), including the human CDH2 gene encoding N-cadherin. At the opposite, pathological AR variants such as AR-V7 associated with prostate tumor progression upregulate those EMT genes. Here, focusing on the human CDH2 gene, we show that this duality between AR and AR-V7 relies on a potential human accelerated region present in the intron 1. This fastest-evolving region of the human genome is actually a variable number tandem repeat (VNTR) comprising 24 repetitions of a DNA sequence that englobes binding sites for steroid hormone receptors, recombination signal binding protein for immunoglobulin kappa j region (RBPJ) an effector of the Notch pathway, and zinc finger e-box binding homeobox 1 (ZEB1). Genomic DNA sequencing, multiple sequence alignment, data mining, as well as protein-DNA interaction and gene expression analyses indicate that this VNTR constitutes a potential transcriptional hub for different transcription factors to control human CDH2 expression. Also, our data suggest that prostate tumor cells may unlock an up to now unknown molecular mechanism associated with a fine-tuned control of human CDH2 gene expression.