The equilibrium of tumor suppression: DUBs as active regulators of PTEN.
The equilibrium of tumor suppression: DUBs as active regulators of PTEN.
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DOI：
10.1038/s12276-022-00887-w
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发表时间：
2022-11
影响因子：
12.8
通讯作者：
Song, Min Sup
中科院分区：
文献类型：
--
作者：
Christine, Audrey;Park, Mi Kyung;Song, Su Jung;Song, Min Sup
PTEN 是人类癌症中最常见丢失或突变的肿瘤抑制基因之一。 PTEN 是一种真正的脂质磷酸酶，可拮抗高度致癌的 PI3K-AKT-mTOR 通路，被认为是主要的剂量依赖性肿瘤抑制因子。尽管 PTEN 功能可能会因遗传综合征和癌症中的基因突变而受到损害，但 PTEN 的翻译后修饰也可能在其功能的动态调节中发挥关键作用。值得注意的是，泛素化和去泛素化失调会对 PTEN 水平和亚细胞分配产生不利影响，从而促进肿瘤发生。虽然 PTEN 可以被 HECT 型 E3 泛素连接酶靶向进行核输入和蛋白酶体降解，但研究表明，几种去泛素化酶，包括 HAUSP/USP7、USP10、USP11、USP13、OTUD3 和 Ataxin-3，可以在癌症特异性环境中从泛素化 PTEN 中去除泛素，从而逆转泛素化介导的 PTEN 调节。研究人员不断揭示 PTEN 癌症特异性去泛素化酶调节其在癌症病理生物学中的作用的精确分子机制，而调节 PTEN 去泛素化酶的新药理学方法是癌症治疗和预防研究的关键领域。在这里，我们评估了去泛素化作为最近被认可的 PTEN 调节模式的机制和功能，并回顾了去泛素化酶和 PTEN 重新激活之间的联系及其对治疗策略的影响。研究重新激活 PTEN 肿瘤抑制蛋白的方法可能有助于寻找新的癌症疗法。 PTEN 抑制信号通路，当该信号通路过度激活时，会强烈影响细胞癌变。尽管一些癌症是由 PTEN 本身的突变引起的，但新的研究表明，称为去泛素酶 (DUB) 的蛋白质可以调节靶蛋白的稳定性和活性，可以打开和关闭 PTEN 活性和癌症。韩国天安市顺天乡大学的 Su Jung Song 和美国休斯敦德克萨斯大学的 Min Sup Song 及其同事回顾了 DUB 如何影响 PTEN，报告了癌症特异性 DUB 的分子机制，并强调了药物靶向 DUB 以增强 PTEN 活性和抑制癌症发展的潜力。这篇综述阐明了一种有前景的开发多种癌症疗法的新方法。
PTEN is among the most commonly lost or mutated tumor suppressor genes in human cancer. PTEN, a bona fide lipid phosphatase that antagonizes the highly oncogenic PI3K-AKT-mTOR pathway, is considered a major dose-dependent tumor suppressor. Although PTEN function can be compromised by genetic mutations in inherited syndromes and cancers, posttranslational modifications of PTEN may also play key roles in the dynamic regulation of its function. Notably, deregulated ubiquitination and deubiquitination lead to detrimental impacts on PTEN levels and subcellular partitioning, promoting tumorigenesis. While PTEN can be targeted by HECT-type E3 ubiquitin ligases for nuclear import and proteasomal degradation, studies have shown that several deubiquitinating enzymes, including HAUSP/USP7, USP10, USP11, USP13, OTUD3 and Ataxin-3, can remove ubiquitin from ubiquitinated PTEN in cancer-specific contexts and thus reverse ubiquitination-mediated PTEN regulation. Researchers continue to reveal the precise molecular mechanisms by which cancer-specific deubiquitinases of PTEN regulate its roles in the pathobiology of cancer, and new methods of pharmacologically for modulating PTEN deubiquitinases are critical areas of investigation for cancer treatment and prevention. Here, we assess the mechanisms and functions of deubiquitination as a recently appreciated mode of PTEN regulation and review the link between deubiquitinases and PTEN reactivation and its implications for therapeutic strategies. Studying ways to reactivate a tumor-suppressing protein called PTEN may help in finding new cancer therapies. PTEN represses a signaling pathway that, when over-activated, strongly influences cells to become cancerous. Although some cancers are caused by mutations of PTEN itself, new research shows that proteins called deubiquitinases (DUBs), which regulate stability and activity of target proteins, can turn on and off PTEN activity and cancer. Su Jung Song at Soonchunhyang University, Cheonan-si, South Korea, and Min Sup Song at The University of Texas, Houston, USA, and coworkers have reviewed how DUBs can affect PTEN, reporting on the molecular mechanisms of cancer-specific DUBs, and highlighting the potential to pharmacologically target DUBs in order to boost PTEN activity and suppress cancer development. This review illuminates a promising new approach to developing therapies for several types of cancer.
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