College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia.
Department of Biochemistry, Faculty of Science, Cancer and Mutagenesis Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Genes (Basel). 2021 Apr 22;12(5):622. doi: 10.3390/genes12050622.
Silencing of tumor suppressor genes (TSGs) through epigenetic mechanisms, mainly via abnormal promoter DNA methylation, is considered a main mechanism of tumorigenesis. The abnormal DNA methylation profiles are transmitted from the cancer mother cell to the daughter cells through the involvement of a macromolecular complex in which the ubiquitin-like containing plant homeodomain (PHD), and an interesting new gene (RING) finger domains 1 (UHRF1), play the role of conductor. Indeed, UHRF1 interacts with epigenetic writers, such as DNA methyltransferase 1 (DNMT1), histone methyltransferase G9a, erasers like histone deacetylase 1 (HDAC1), and functions as a hub protein. Thus, targeting UHRF1 and/or its partners is a promising strategy for epigenetic cancer therapy. The natural compound thymoquinone (TQ) exhibits anticancer activities by targeting several cellular signaling pathways, including those involving UHRF1. In this review, we highlight TQ as a potential multitarget single epidrug that functions by targeting the UHRF1/DNMT1/HDAC1/G9a complex. We also speculate on the possibility that TQ might specifically target UHRF1, with subsequent regulatory effects on other partners.
通过表观遗传机制（主要通过异常启动子 DNA 甲基化）沉默肿瘤抑制基因（TSGs）被认为是肿瘤发生的主要机制。异常的 DNA 甲基化谱通过涉及一种包含泛素样结构域的植物同源域（PHD）和一个有趣的新基因（RING）指状结构域 1（UHRF1）的大分子复合物，从癌细胞母细胞传递到子细胞。事实上，UHRF1 与表观遗传写入器（如 DNA 甲基转移酶 1（DNMT1）、组蛋白甲基转移酶 G9a）相互作用，是一种枢纽蛋白。因此，靶向 UHRF1 和/或其伴侣是表观遗传癌症治疗的一种很有前途的策略。天然化合物百里醌（TQ）通过靶向包括 UHRF1 在内的几种细胞信号通路来发挥抗癌作用。在这篇综述中，我们强调 TQ 是一种潜在的多靶单一表药物，通过靶向 UHRF1/DNMT1/HDAC1/G9a 复合物发挥作用。我们还推测 TQ 可能特异性地靶向 UHRF1，随后对其他伴侣产生调节作用。
