Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China.
Sci Adv. 2020 Apr 29;6(18):eaaz8031. doi: 10.1126/sciadv.aaz8031. eCollection 2020 May.
The orphan nuclear receptor COUP-TFII is expressed at a low level in adult tissues, but its expression is increased and shown to promote progression of multiple diseases, including prostate cancer, heart failure, and muscular dystrophy. Suppression of COUP-TFII slows disease progression, making it an intriguing therapeutic target. Here, we identified a potent and specific COUP-TFII inhibitor through high-throughput screening. The inhibitor specifically suppressed COUP-TFII activity to regulate its target genes. Mechanistically, the inhibitor directly bound to the COUP-TFII ligand-binding domain and disrupted COUP-TFII interaction with transcription regulators, including FOXA1, thus repressing COUP-TFII activity on target gene regulation. Through blocking COUP-TFII's oncogenic activity in prostate cancer, the inhibitor efficiently exerted a potent antitumor effect in xenograft mouse models and patient-derived xenograft models. Our study identified a potent and specific COUP-TFII inhibitor that may be useful for the treatment of prostate cancer and possibly other diseases.
孤儿核受体 COUP-TFII 在成人组织中的表达水平较低，但它的表达会增加，并被证明会促进多种疾病的进展，包括前列腺癌、心力衰竭和肌肉萎缩症。抑制 COUP-TFII 可减缓疾病进展，使其成为一个有趣的治疗靶点。在这里，我们通过高通量筛选鉴定出一种有效的、特异性的 COUP-TFII 抑制剂。该抑制剂特异性地抑制 COUP-TFII 活性，从而调节其靶基因。从机制上讲，该抑制剂直接与 COUP-TFII 的配体结合域结合，并破坏 COUP-TFII 与转录调节剂（包括 FOXA1）的相互作用，从而抑制 COUP-TFII 对靶基因调控的活性。通过在前列腺癌中阻断 COUP-TFII 的致癌活性，该抑制剂在异种移植小鼠模型和患者来源的异种移植模型中有效地发挥了强大的抗肿瘤作用。我们的研究鉴定出一种有效的、特异性的 COUP-TFII 抑制剂，可能对治疗前列腺癌和其他疾病有用。
