Disulfiram and 6-Thioguanine synergistically inhibit the enzymatic activities of USP2 and USP21

Lin, Hsin Cheng; Kuan, Ying; Chu, Hsu Feng; Cheng, Shu; Pan, Heng; Chen, Wei Yi; Sun, Chaomin; Lin, Ta Hsien

doi:10.1016/j.ijbiomac.2021.02.072

Cited by 16 publications

(11 citation statements)

References 39 publications

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“…The 2-year survival rate was approximately 35% for most patients, and the 2-year survival rate of some subtypes is Computational and Mathematical Methods in Medicine even below 5% [5]. Acute myeloid leukemia has a long treatment cycle, painful treatment process, high recurrence rate, and low survival rate, which bring great pain and economic burden to patients and their families [6]. Therefore, according to the heterogeneity of LAML patients, screening effective drug targets for the treatment of acute myeloid leukemia provides a new possibility.…”

Section: Introductionmentioning

confidence: 99%

Expression and Regulation Network of HDAC3 in Acute Myeloid Leukemia and the Implication for Targeted Therapy Based on Multidataset Data Mining

Lan

et al. 2022

Computational and Mathematical Methods in Medicine

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Background. Histone deacetylase 3 (HDAC3) plays an important role in the development and progression of a variety of cancers, but its regulatory mechanism in acute myeloid leukemia (LAML) is not entirely understood. Methods. We analyzed the expression of HDAC3 in normal and cancerous tissues using Oncomine, UALCAN, and GEO databases. Changes of the HDAC3 gene were analyzed by cBioPortal. The genes coexpressed with HDAC3 were analyzed by WebGestalt, and the predicted signaling pathways in KEGG were discussed. Results. We discovered that the expression of HDAC3 was elevated in some types of acute myeloid leukemia. The HDAC3 gene has a strong positive correlation with SLC25A5, NDUFA2, Cox4I1, and EIF3K, which regulate cell growth and development. HDAC3 transcription is higher in patients with FLT3 mutation than in healthy people. HDAC3 can be directly involved in regulating the thyroid hormone signaling pathway. MEF2D is directly involved in the cGMP-PKG signaling pathway, and the HDAC3 gene has a strong synergistic relationship with MEF2D. HDAC3 is indirectly involved in the cGMP-PKG signaling pathway, thereby indirectly regulating the expression levels of p53 and p21 genes in patients with LAML. Genomics of Drug Sensitivity in Cancer (GDSC) database analysis revealed that the application of the HDAC3 inhibitor can inhibit the proliferation of leukemia cells. Conclusions. Therefore, our data suggest that HDAC3 may be a possible therapeutic target for acute myeloid leukemia.

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Section: Introductionmentioning

confidence: 99%

Expression and Regulation Network of HDAC3 in Acute Myeloid Leukemia and the Implication for Targeted Therapy Based on Multidataset Data Mining

Lan

et al. 2022

Computational and Mathematical Methods in Medicine

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“…A recent study has shown that disulfiram, a clinically used anti-alcoholism drug, could function as a potent inhibitor of USP21 [ 31 ]. In order to corroborate our USP21-knockdown findings, we assessed whether disulfiram also abrogates USP21-mediated FOXD1 stabilization.We first determined whether disulfiram could block the deubiquitinating activities of USP21.…”

Section: Resultsmentioning

confidence: 99%

USP21 promotes self-renewal and tumorigenicity of mesenchymal glioblastoma stem cells by deubiquitinating and stabilizing FOXD1

et al. 2022

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Recent studies suggest that Forkhead box D1 (FOXD1) plays an indispensable role in maintaining the mesenchymal (MES) properties of glioblastoma (GBM) stem cells (GSCs). Thus, understanding the mechanisms that control FOXD1 protein expression is critical for guiding GBM treatment, particularly in patients with therapy-resistant MES subtypes. In this study, we identify the ubiquitin-specific peptidase 21 (USP21) as a critical FOXD1 deubiquitinase in MES GSCs. We find that USP21 directly interacts with and stabilizes FOXD1 by reverting its proteolytic ubiquitination. Silencing of USP21 enhances polyubiquitination of FOXD1, promotes its proteasomal degradation, and ultimately attenuates MES identity in GSCs, while these effects could be largely restored by reintroduction of FOXD1. Remarkably, we show that disulfiram, a repurposed drug that could block the enzymatic activities of USP21, suppresses GSC tumorigenicity in MES GSC-derived GBM xenograft model. Additionally, we demonstrate that USP21 is overexpressed and positively correlated with FOXD1 protein levels in GBM tissues, and its expression is inversely correlated with patient survival. Collectively, our work reveals that USP21 maintains MES identity by antagonizing FOXD1 ubiquitination and degradation, suggesting that USP21 is a potential therapeutic target for the MES subtype of GBM.

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“…Disulfiram, an anti-alcohol abuse drug actively being repurposed for cancer, and 6-Thioguanine (6 TG), a clinical drug for acute myeloid leukemia, were recently identified as competitive inhibitors of USP21 ( Table 5 ). Co-treatment with disulfiram and 6 TG exhibited a synergistic effect of USP21 inhibition, indicating that these two drugs may modify cysteine residues in different regions of USP21 ( Lin et al, 2021 ). This encourages the evaluation of combination treatment with disulfiram and 6 TG for USP21 dysregulated diseases including cancer.…”

Section: Inhibitors Of Usp21mentioning

confidence: 99%

“…This encourages the evaluation of combination treatment with disulfiram and 6 TG for USP21 dysregulated diseases including cancer. Furthermore, disulfiram and 6 TG synergistically inhibited the enzymatic activity of USP2 ( Lin et al, 2021 ), but whether these two compounds suppress the activity of other DUBs remains to be studied further. Moreover, two other non-selective small-molecule inhibitors of USP21, spongiacidin C and KYT-36, have been reported ( Table 5 ).…”

Section: Inhibitors Of Usp21mentioning

confidence: 99%

Insights Into the Properties, Biological Functions, and Regulation of USP21

et al. 2022

Front. Pharmacol.

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Deubiquitylating enzymes (DUBs) antagonize ubiquitination by removing ubiquitin from their substrates. The role of DUBs in controlling various physiological and pathological processes has been extensively studied, and some members of DUBs have been identified as potential therapeutic targets in diseases ranging from tumors to neurodegeneration. Ubiquitin-specific protease 21 (USP21) is a member of the ubiquitin-specific protease family, the largest subfamily of DUBs. Although USP21 was discovered late and early research progress was slow, numerous studies in the last decade have gradually revealed the importance of USP21 in a wide variety of biological processes. In particular, the pro-carcinogenic effect of USP21 has been well elucidated in the last 2 years. In the present review, we provide a comprehensive overview of the current knowledge on USP21, including its properties, biological functions, pathophysiological roles, and cellular regulation. Limited pharmacological interventions for USP21 have also been introduced, highlighting the importance of developing novel and specific inhibitors targeting USP21.

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Disulfiram and 6-Thioguanine synergistically inhibit the enzymatic activities of USP2 and USP21

Cited by 16 publications

References 39 publications

Expression and Regulation Network of HDAC3 in Acute Myeloid Leukemia and the Implication for Targeted Therapy Based on Multidataset Data Mining

Expression and Regulation Network of HDAC3 in Acute Myeloid Leukemia and the Implication for Targeted Therapy Based on Multidataset Data Mining

USP21 promotes self-renewal and tumorigenicity of mesenchymal glioblastoma stem cells by deubiquitinating and stabilizing FOXD1

Insights Into the Properties, Biological Functions, and Regulation of USP21

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