Diosgenin inhibits prostate cancer progression by inducing UHRF1 protein degradation
Diosgenin inhibits prostate cancer progression by inducing UHRF1 protein degradation
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薯蓣皂苷元通过诱导 UHRF1 蛋白降解抑制前列腺癌进展
DOI：
10.1016/j.ejphar.2023.175522
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发表时间：
2023
影响因子：
5
通讯作者：
Xiong Li
中科院分区：
文献类型：
--
作者：
Yuchong Peng;Rong Tang;Liuyang Ding;Rirong Zheng;Youhong Liu;Linglong Yin;Yongming Fu;Tanggang Deng;Xiong Li
前列腺癌是成年男子癌症死亡的第二大原因。UHRF1的异常过表达已在几种癌症类型中被报道，并被认为是癌症治疗的新药物靶点。然而，目前还没有针对uhrf1的小分子抑制剂在临床试验中进行测试。中药方剂治疗PCa在中国有着悠久的历史，中药提取物是新药发现的重要资源。在本研究中，我们首先利用网络药理学结合分子对接技术，从临床常用中药中筛选出治疗PCa的潜在有效成分。我们鉴定出薯蓣皂苷元（DSG）是一种特异性靶向UHRF1蛋白的天然小分子化合物。此外，我们还通过湿室实验验证了结果。DSG通过直接结合UHRF1蛋白，通过泛素-蛋白酶体途径诱导UHRF1蛋白降解。重要的是，DSG通过减少蛋白与去泛素酶USP7的相互作用诱导UHRF1蛋白降解。DSG降低基因组DNA甲基化水平，提高p21、p16、LXN等肿瘤抑制基因的表达，从而导致细胞周期阻滞、细胞衰老，抑制异种移植肿瘤生长。我们首次报道了DSG特异性诱导UHRF1蛋白降解，从而揭示了DSG的一种新的抗癌机制。总之，本研究为从小分子天然产物中发现新的分子靶向药物提供了一个有希望的策略。
Prostate cancer (PCa) represents the second cause of cancer death in adult men. Aberrant overexpression of UHRF1 has been reported in several cancer types, and is regarded as a novel drug target for cancer therapy. Nevertheless, no UHRF1-targeted small molecule inhibitor has been testing in clinical trials. Traditional Chinese medicine (TCM) prescriptions have a long history for the treatment of PCa in China, and Chinese herbal extracts are important resources for new drug discovery. In the present study, we first screened the potentially effective components from the commonly used TCMs for PCa treatment in clinic by using network pharmacology together with molecular docking. We identified diosgenin (DSG) as a small molecule natural compound specifically targeting UHRF1 protein. Furthermore, we validated the results by using the wet lab experiments. DSG, by directly binding UHRF1 protein, induced UHRF1 protein degradation through the ubiquitin-proteasome pathway. Importantly, DSG induced UHRF1 protein degradation by reducing the protein interaction with a deubiquitinase USP7. DSG reduced the level of genomic DNA methylation, and elevated the expression of such tumor suppressor genes as p21, p16 and LXN, thereby resulting in cell cycle arrest, cellular senescence and the inhibition of xenograft tumor growth. We here presented the first report that DSG specifically induced UHRF1 protein degradation, thereby revealing a novel anticancer mechanism of DSG. Altogether, this present study provided a promising strategy to discover new molecule-targeted drugs from small-molecule natural products.