Erdmann Éva, Agolli Savera, Fix Simon, Cottard Félicie, Keyser Christine, Zvenigorosky Vincent, Gonzalez Angéla, Haili Zakary, Kieffer Bruno, Céraline Jocelyn
CNRS UMR 7104, INSERM U1258, IGBMC, Université de Strasbourg, Illkirch, 67404, France.
CNRS UMR 7242, ESBS, Université de Strasbourg, Illkirch, 67404, France.
Cell Mol Life Sci. 2025 May 9;82(1):196. doi: 10.1007/s00018-025-05725-6.
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.
雄激素受体（AR）是核受体超家族的成员，它通过抑制一组参与上皮-间质转化（EMT）的基因来控制前列腺上皮细胞的可塑性，这些基因包括编码N-钙黏蛋白的人类CDH2基因。相反，与前列腺肿瘤进展相关的病理性AR变体，如AR-V7，则会上调这些EMT基因。在此，我们聚焦于人类CDH2基因，发现AR和AR-V7之间的这种双重性依赖于内含子1中存在的一个潜在人类加速区域。人类基因组中这个进化最快的区域实际上是一个可变数目串联重复序列（VNTR），它由一段DNA序列重复24次组成，该序列包含类固醇激素受体的结合位点、免疫球蛋白κ轻链基因结合区重组信号结合蛋白（RBPJ，Notch信号通路的一个效应因子）以及锌指E盒结合同源框蛋白1（ZEB1）的结合位点。基因组DNA测序、多序列比对、数据挖掘以及蛋白质-DNA相互作用和基因表达分析表明，这个VNTR构成了一个潜在的转录枢纽，不同转录因子可通过它来控制人类CDH2的表达。此外，我们的数据表明，前列腺肿瘤细胞可能开启了一种迄今为止未知的分子机制，该机制与人类CDH2基因表达的精细调控有关。
