SUMO Losing Balance: SUMO Proteases Disrupt SUMO Homeostasis to Facilitate Cancer Development and Progression.
SUMO Losing Balance: SUMO Proteases Disrupt SUMO Homeostasis to Facilitate Cancer Development and Progression.
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DOI：
10.1177/1947601910382555
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发表时间：
2010-07
期刊：
影响因子：
--
通讯作者：
Yeh ET
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文献类型：
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作者：
Bawa-Khalfe T;Yeh ET
小泛素样修饰物（SUMO）与细胞蛋白质的缀合是一种可逆的翻译后修饰，其介导蛋白质的功能、亚细胞定位和/或表达。SUMO蛋白酶（SENP）使修饰的蛋白质去缀合，因此对于维持正常生理学所需的SUMO化和非SUMO化底物的水平至关重要。在几种癌中观察到SENP的表达改变。本文综述了SENP水平的变化如何干扰SUMO稳态，并有助于癌症的发展和进展。我们报道了SENP家族的一个成员，SENP 1可以将正常的前列腺上皮转化为发育异常状态，并直接调节前列腺细胞中的几种致癌途径，包括AR，c-Jun和Cyclin D1。对来自人前列腺癌患者的组织的评估表明SENP 1和SUMO 2/3解结合酶SENP 3的mRNA水平升高。SENP 3在癌细胞中的诱导启动了血管生成途径;特别是SENP 3通过共调节蛋白p300的去SUMO化来调节缺氧诱导因子1α（HIF 1 α）的转录活性。与前列腺癌不同，增强的SUMO化有利于乳腺癌的发生，并与在几种乳腺癌组织阵列中发现的SENP 6 mRNA水平降低相关。预防乳腺癌细胞中细胞底物的SUMO结合增强可减少肿瘤发生。因此，SUMO平衡的扭曲有助于癌症的发生和发展，特别是在前列腺癌和乳腺癌中。去SUMO化机制可能是恢复SUMO系统平衡的关键，因此可以作为治疗药物的理想靶点。
Small ubiquitin-like modifiers (SUMO) conjugation to cellular proteins is a reversible posttranslational modification that mediates the protein’s function, subcellular localization, and/or expression. The SUMO proteases (SENP) deconjugate modified proteins and thus are critical for maintaining the level of SUMOylated and un-SUMOylated substrates required for normal physiology. Altered expression of SENPs is observed in several carcinomas. This review focuses on how the change in SENP levels disturbs SUMO homeostasis and contributes to cancer development and progression. We reported that one member of the SENP family, SENP1 can transform normal prostate epithelia to a dysplasic state and directly modulate several oncogenic pathways in prostate cells, including AR, c-Jun, and Cyclin D1. Assessment of tissue from human prostate cancer patients indicates elevated mRNA levels of SENP1 and the SUMO2/3 deconjugating enzyme, SENP3. The induction of SENP3 in cancer cells initiates the angiogenic pathway; specifically SENP3 regulates the transcriptional activity of hypoxia-inducible factor 1α (HIF1α) via deSUMOylation of the co-regulatory protein p300. Unlike prostate cancer, enhanced SUMOylation is favored with onset of breast cancer and correlated with the reduced SENP6 mRNA levels found in several breast cancer tissue arrays. Preventing enhanced SUMO conjugation of cellular substrates in breast cancer cells reduces tumorigenesis. Hence, distortion of SUMO equilibrium contributes to both the initiation and progression of cancer, specifically in prostate and breast cancers. The deSUMOylation machinery may be key to restoring balance to the SUMO system and hence serve as ideal targets for therapeutic agents.