Blockade of deubiquitinase YOD1 degrades oncogenic PML/RARα and eradicates acute promyelocytic leukemia cells.
Blockade of deubiquitinase YOD1 degrades oncogenic PML/RARα and eradicates acute promyelocytic leukemia cells.
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DOI：
10.1016/j.apsb.2021.10.020
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发表时间：
2022-04
影响因子：
14.5
通讯作者：
Ying, Meidan
中科院分区：
文献类型：
--
作者：
Shao, Xuejing;Chen, Yingqian;Wang, Wei;Du, Wenxin;Zhang, Xingya;Cai, Minyi;Bing, Shaowei;Cao, Ji;Xu, Xiaojun;Yang, Bo;He, Qiaojun;Ying, Meidan
关键词：
In most acute promyelocytic leukemia (APL) cells, promyelocytic leukemia (PML) fuses to retinoic acid receptor α (RARα) due to chromosomal translocation, thus generating PML/RARα oncoprotein, which is a relatively stable oncoprotein for degradation in APL. Elucidating the mechanism regulating the stability of PML/RARα may help to degrade PML/RARα and eradicate APL cells. Here, we describe a deubiquitinase (DUB)-involved regulatory mechanism for the maintenance of PML/RARα stability and develop a novel pharmacological approach to degrading PML/RARα by inhibiting DUB. We utilized a DUB siRNA library to identify the ovarian tumor protease (OTU) family member deubiquitinase YOD1 as a critical DUB of PML/RARα. Suppression of YOD1 promoted the degradation of PML/RARα, thus inhibiting APL cells and prolonging the survival time of APL cell-bearing mice. Subsequent phenotypic screening of small molecules allowed us to identify ubiquitin isopeptidase inhibitor I (G5) as the first YOD1 pharmacological inhibitor. As expected, G5 notably degraded PML/RARα protein and eradicated APL, particularly drug-resistant APL cells. Importantly, G5 also showed a strong killing effect on primary patient-derived APL blasts. Overall, our study not only reveals the DUB-involved regulatory mechanism on PML/RARα stability and validates YOD1 as a potential therapeutic target for APL, but also identifies G5 as a YOD1 inhibitor and a promising candidate for APL, particularly drug-resistant APL treatment. Deubiquitinase YOD1 is responsible for cleaving polyubiquitin chains for PML/RARα to escape from ubiquitin-dependent degradation. G5 as the first YOD1 inhibitor degrades PML/RARα to suppress drug-resistant APL progression.
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DOI：
10.1038/nrd.2017.152
发表时间：
2018-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Harrigan JA;Jacq X;Martin NM;Jackson SP
通讯作者：
Jackson SP
影响因子：
3.7
作者：
Drayson, MT;Michell, RH;Brown, G
通讯作者：
Brown, G
影响因子：
20.3
作者：
Goto, Emi;Tomita, Akihiro;Naoe, Tomoki
通讯作者：
Naoe, Tomoki
影响因子：
48
作者：
Auslander, David;Auslander, Simon;Fussenegger, Martin
通讯作者：
Fussenegger, Martin
影响因子：
11.4
作者：
Cheung, A. M. S.;Wan, T. S. K.;Leung, A. Y. H.
通讯作者：
Leung, A. Y. H.