Laboratório de Genética e Biotecnologia, Instituto de Biotecnologia, Universidade Federal de Uberlândia, Patos de Minas, MG, Brasil.
Laboratório de Nanobiotechnologia Prof. Dr. Luiz Ricardo Goulart Filho, Instituto de Biotechnologia, Universidade Federal de Uberlândia, Uberlândia, MG, Brasil.
Braz J Med Biol Res. 2024 Jun 17;57:e13190. doi: 10.1590/1414-431X2024e13190. eCollection 2024.
The overexpression of the prostate cancer antigen 3 (PCA3) gene is well-defined as a marker for prostate cancer (PCa) diagnosis. Although widely used in clinical research, PCA3 molecular mechanisms remain unknown. Herein we used phage display technology to identify putative molecules that bind to the promoter region of PCA3 gene and regulate its expression. The most frequent peptide PCA3p1 (80%) was similar to the Rho GTPase activating protein 21 (ARHGAP21) and its binding affinity was confirmed using Phage Bead ELISA. We showed that ARHGAP21 silencing in LNCaP prostate cancer cells decreased PCA3 and androgen receptor (AR) transcriptional levels and increased prune homolog 2 (PRUNE2) coding gene expression, indicating effective involvement of ARHGAP21 in androgen-dependent tumor pathway. Chromatin immunoprecipitation assay confirmed the interaction between PCA3 promoter region and ARHGAP21. This is the first study that described the role of ARHGAP21 in regulating the PCA3 gene under the androgenic pathway, standing out as a new mechanism of gene regulatory control during prostatic oncogenesis.
前列腺癌抗原 3（PCA3）基因的过表达被明确为前列腺癌（PCa）诊断的标志物。尽管 PCA3 在临床研究中得到广泛应用，但 PCA3 的分子机制仍不清楚。在此，我们使用噬菌体展示技术鉴定与 PCA3 基因启动子区结合并调节其表达的假定分子。最频繁的肽 PCA3p1（80%）与 Rho GTPase 激活蛋白 21（ARHGAP21）相似，其结合亲和力通过 Phage Bead ELISA 得到确认。我们表明，LNCaP 前列腺癌细胞中 ARHGAP21 的沉默降低了 PCA3 和雄激素受体（AR）转录水平，并增加了修剪同源物 2（PRUNE2）编码基因的表达，表明 ARHGAP21 有效参与了雄激素依赖性肿瘤途径。染色质免疫沉淀分析证实了 PCA3 启动子区域与 ARHGAP21 之间的相互作用。这是第一项描述 ARHGAP21 在雄激素途径下调 PCA3 基因的作用的研究，它突出了前列腺癌发生过程中基因调控控制的新机制。
