Department of Molecular Bioscience, College of Biomedical Sciences, Kangwon National University, Chuncheon 24341, Korea.
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792, Korea.
Int J Mol Sci. 2019 Apr 4;20(7):1684. doi: 10.3390/ijms20071684.
Four members of the retinoic acid-related orphan receptor α (RORα) family (RORα1, RORα2, RORα3 and RORα4) are transcription factors that regulate several processes including circadian rhythm, lipid metabolism, cerebellar development, immune function, and cancer. Only two isoforms, RORα1 and 4, are specifically co-expressed in the murine and human. In the present study, we identified a specific N-terminal domain (NTD) of RORα1 that potentiated the downregulation of target genes involved in tumor progression and proliferation, based on results from RORα-deficient mouse embryonic fibroblasts and prostate carcinoma tissues. The hyperactivation of proliferative target genes were observed in RORα-deficient embryonic fibroblasts, and reconstitution of RORα1 inhibited this activation by a NTD dependent manner. Downregulation of RORα1 and upregulation of Wnt/β-catenin target genes were correlated in prostate cancer patients. These findings revealed the control of invasive growth by NTD-mediated RORα1 signaling, suggesting advanced approaches for the development of therapeutic drugs.
视黄酸相关孤儿受体 α（RORα）家族的四个成员（RORα1、RORα2、RORα3 和 RORα4）是转录因子，可调节包括昼夜节律、脂质代谢、小脑发育、免疫功能和癌症在内的多个过程。只有两种异构体，RORα1 和 4，在鼠和人中特异性共表达。在本研究中，我们基于 RORα 缺陷型小鼠胚胎成纤维细胞和前列腺癌组织的结果，鉴定了 RORα1 的特定 N 端结构域（NTD），该结构域可增强涉及肿瘤进展和增殖的靶基因的下调。在 RORα 缺陷型胚胎成纤维细胞中观察到增殖靶基因的过度激活，并且 RORα1 的重建以 NTD 依赖性方式抑制了这种激活。在前列腺癌患者中，RORα1 的下调和 Wnt/β-catenin 靶基因的上调相关。这些发现揭示了 NTD 介导的 RORα1 信号对侵袭性生长的控制，为开发治疗药物提供了新的方法。
