Shao Xuejing, Chen Yingqian, Wang Wei, Du Wenxin, Zhang Xingya, Cai Minyi, Bing Shaowei, Cao Ji, Xu Xiaojun, Yang Bo, He Qiaojun, Ying Meidan
Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Cancer Center, Zhejiang University, Hangzhou 310058, China.
Acta Pharm Sin B. 2022 Apr;12(4):1856-1870. doi: 10.1016/j.apsb.2021.10.020. Epub 2021 Oct 23.
In most acute promyelocytic leukemia (APL) cells, promyelocytic leukemia (PML) fuses to retinoic acid receptor (RAR) due to chromosomal translocation, thus generating PML/RAR oncoprotein, which is a relatively stable oncoprotein for degradation in APL. Elucidating the mechanism regulating the stability of PML/RAR may help to degrade PML/RAR and eradicate APL cells. Here, we describe a deubiquitinase (DUB)-involved regulatory mechanism for the maintenance of PML/RAR stability and develop a novel pharmacological approach to degrading PML/RAR 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/RAR. Suppression of YOD1 promoted the degradation of PML/RAR, 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/RAR 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/RAR 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.
在大多数急性早幼粒细胞白血病（APL）细胞中，由于染色体易位，早幼粒细胞白血病（PML）与维甲酸受体（RAR）融合，从而产生PML/RAR癌蛋白，这是一种在APL中相对稳定、不易降解的癌蛋白。阐明调节PML/RAR稳定性的机制可能有助于降解PML/RAR并根除APL细胞。在此，我们描述了一种涉及去泛素化酶（DUB）的维持PML/RAR稳定性的调控机制，并开发了一种通过抑制DUB来降解PML/RAR的新型药理学方法。我们利用一个DUB siRNA文库鉴定出卵巢肿瘤蛋白酶（OTU）家族成员去泛素化酶YOD1是PML/RAR的关键DUB。抑制YOD1可促进PML/RAR的降解，从而抑制APL细胞并延长携带APL细胞的小鼠的存活时间。随后对小分子进行表型筛选，使我们鉴定出泛素异肽酶抑制剂I（G5）作为首个YOD1药理学抑制剂。正如预期的那样，G5显著降解PML/RAR蛋白并根除APL，尤其是耐药APL细胞。重要的是，G5对原发性患者来源的APL原始细胞也显示出强大的杀伤作用。总体而言，我们的研究不仅揭示了涉及DUB的PML/RAR稳定性调控机制，并验证YOD1作为APL的潜在治疗靶点，还鉴定出G5作为YOD1抑制剂以及APL，尤其是耐药APL治疗的有前景的候选药物。
