The epigenetic regulator UHRF1 promotes ubiquitination-mediated degradation of the tumor-suppressor protein promyelocytic leukemia protein.
The epigenetic regulator UHRF1 promotes ubiquitination-mediated degradation of the tumor-suppressor protein promyelocytic leukemia protein.
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DOI：
10.1038/onc.2012.406
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发表时间：
2013-08-15
期刊：
影响因子：
8
通讯作者：
Kao, H-Y
中科院分区：
文献类型：
--
作者：
Guan, D.;Factor, D.;Liu, Yu;Wang, Z.;Kao, H-Y
早幼粒细胞白血病（PML）蛋白是最初在急性早幼粒细胞白血病中鉴定的肿瘤抑制物，并且涉及多种形式的癌症的肿瘤发生。在这里，我们证明了PML蛋白经历了由E3连接酶UHRF 1（具有PHD和RING指结构域1的泛素样蛋白）促进的泛素化介导的降解，该酶通常在各种人类恶性肿瘤中上调。此外，UHRF 1负调节PML蛋白在原代人脐静脉内皮细胞（HUVEC）、HEK 293细胞和癌细胞中的积累。UHRF 1的敲除上调，而UHRF 1的异位过表达下调内源性或外源性PML的蛋白丰度，这是通过其与PML的N末端结合来实现的。野生型UHRF1的过表达缩短了PML蛋白的半衰期并促进PML多聚泛素化，而RING结构域的缺失或显性负性E2泛素缀合酶E2D2的共表达减弱了这种对PML的修饰。最后，UHRF1的敲除延长了PML半衰期并增加了PML蛋白的积累，但抑制了细胞迁移和体外毛细血管形成，而PML的共敲除则损害了这种抑制作用。这些发现表明，UHRF 1促进PML蛋白的周转，因此靶向UHRF 1以恢复PML介导的肿瘤抑制代表了一种有前途的新型抗癌策略。
The promyelocytic leukemia (PML) protein is a tumor suppressor originally identified in acute promyelocytic leukemia and implicated in tumorigenesis in multiple forms of cancer. Here, we demonstrate that the PML protein undergoes ubiquitination-mediated degradation facilitated by an E3 ligase UHRF1 (ubiquitin-like with PHD and RING finger domains 1), which is commonly upregulated in various human malignancies. Furthermore, UHRF1 negatively regulates PML protein accumulation in primary human umbilical vein endothelial cells (HUVECs), HEK 293 cells and cancer cells. Knockdown of UHRF1 upregulates whereas ectopic overexpression of UHRF1 downregulates protein abundance of endogenous or exogenous PML, doing so through its binding to the N-terminus of PML. Overexpression of wild-type UHRF1 shortens PML protein half-life and promotes PML polyubiquitination, whereas deletion of the RING domain or coexpression of the dominant-negative E2 ubiquitin-conjugating enzyme, E2D2, attenuates this modification to PML. Finally, knockdown of UHRF1 prolongs PML half-life and increases PML protein accumulation, yet inhibits cell migration and in vitro capillary tube formation, whereas co-knockdown of PML compromises this inhibitory effect. These findings suggest that UHRF1 promotes the turnover of PML protein, and thus targeting UHRF1 to restore PML-mediated tumor suppression represents a promising, novel, anticancer strategy.
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