Targeting the SET and RING-associated (SRA) domain of ubiquitin-like, PHD and ring finger-containing 1 (UHRF1) for anti-cancer drug development.
Targeting the SET and RING-associated (SRA) domain of ubiquitin-like, PHD and ring finger-containing 1 (UHRF1) for anti-cancer drug development.
复制标题
针对泛素蛋白样，博士学位和含环的1（UHRF1）的集合和环相关（SRA）结构域，以进行抗癌药物开发。
DOI：
10.18632/oncotarget.25425
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发表时间：
2018-05-25
期刊：
影响因子：
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通讯作者：
Pradhan S
中科院分区：
文献类型：
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作者：
Patnaik D;Estève PO;Pradhan S
含有泛素样的PHD环指1（UHRF 1）是具有甲基DNA结合SRA（SET和RING相关）结构域的多结构域蛋白，其是由DNMT 1介导的维持DNA甲基化所需的。UHRF 1主要在增殖细胞中表达，是进入S期所需的细胞周期调节蛋白。此外，UHRF 1通过连接DNA甲基化和组蛋白修饰参与转录基因调控。UHRF 1的上调可作为多种癌症的生物标志物;包括乳腺癌、胃癌、前列腺癌、肺癌和结肠直肠癌。为此，UHRF 1的过表达通过触发DNA甲基化的异常模式促进癌症转移，并随后沉默肿瘤抑制基因。文献中已经报道了UHRF 1的各种小分子效应物，尽管作用机制可能没有完全表征。可能与SRA结构域结合的小分子可能会影响UHRF 1结合半甲基化DNA的能力，从而减少异常的DNA甲基化。因此，在癌症的一个子集中，小分子UHRF 1抑制剂可以恢复正常的基因表达，并作为有用的抗癌治疗剂。
Ubiquitin-like containing PHD Ring Finger 1 (UHRF1) is a multi-domain protein with a methyl-DNA binding SRA (SET and RING-associated) domain, required for maintenance DNA methylation mediated by DNMT1. Primarily expressed in proliferating cells, UHRF1 is a cell-cycle regulated protein that is required for S phase entry. Furthermore, UHRF1 participates in transcriptional gene regulation by connecting DNA methylation to histone modifications. Upregulation of UHRF1 may serve as a biomarker for a variety of cancers; including breast, gastric, prostate, lung and colorectal carcinoma. To this end, overexpression of UHRF1 promotes cancer metastasis by triggering aberrant patterns of DNA methylation, and subsequently, silencing tumor suppressor genes. Various small molecule effectors of UHRF1 have been reported in the literature, although the mechanism of action may not be fully characterized. Small molecules that potentially bind to the SRA domain may affect the ability of UHRF1 to bind hemimethylated DNA; thereby reducing aberrant DNA methylation. Therefore, in a subset of cancers, small molecule UHRF1 inhibitors may restore normal gene expression and serve as useful anti-cancer therapeutics.