Blockade of deubiquitinase YOD1 degrades oncogenic PML/RAR α and eradicates acute promyelocytic leukemia cells

  • Acta Pharm Sin B. 2022 Apr;12(4):1856-1870. doi: 10.1016/j.apsb.2021.10.020.
Xuejing Shao  1 ,  Yingqian Chen  1 ,  Wei Wang  1 ,  Wenxin Du  1 ,  Xingya Zhang  1 ,  Minyi Cai  1 ,  Shaowei Bing  1 ,  Ji Cao  1  2  3 ,  Xiaojun Xu  4 ,  Bo Yang  1  3 ,  Qiaojun He  1  2  3 ,  Meidan Ying  1  4  2
Affiliations
  • 1. Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 2. Cancer Center, Zhejiang University, Hangzhou 310058, China.
  • 3. Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310058, China.
  • 4. Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China.
PMID: 35847510 DOI: 10.1016/j.apsb.2021.10.020
Abstract

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.

Keywords
APL, acute promyelocytic leukemia; ATO, arsenic trioxide; ATRA, all-trans retinoic acid; Acute promyelocytic leukemia; Degradation; Deubiquitinase; Drug resistance; EARD, endoplasmic reticulum-associated degradation; FLT3/ITD, internal tandem duplication within FLT3; G5, ubiquitin isopeptidase inhibitor I; HOTAIRM1, HOXA transcript antisense RNA myeloid-specific 1; Inhibitor; JAMM, Jab1/Pab1/MPN domain-containing protease; LATS, large tumor suppressor kinase; MDM2, murine double minute 2; MINDY, motif-interacting with ubiquitin-containing novel DUB family; MJD, machado-Joseph domain-containing protease; OUT, ovarian tumor; PLZF, promyelocytic leukemia zinc finger; PML, promyelocytic leukemia; PML/RARα; RARα, retinoic acid receptor α; RNF4, ring finger protein 4; S100A3, S100 calcium binding protein A3; TAZ, transcriptional co-activator with PDZ-binding motif; TGFβ, transforming growth factor β; TRIB3, tribbles pseudokinase 3; Therapy; UCH, ubiquitin carboxyl terminal hydrolase; UCHL1, ubiquitin c-terminal hydrolase L1; USP, ubiquitin specific protease; YAP, yes-associated protein; YOD1; cAMP, cyclic adenosine monophosphate.
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