scholarly journals Deubiquitinating enzyme inhibitor alleviates cyclin A1‐mediated proteasome inhibitor tolerance in mixed‐lineage leukemia

2021 ◽  
Author(s):  
Maolin Ge ◽  
Qiongyu Xu ◽  
Ting Kang ◽  
Dan Li ◽  
Ruiheng Wang ◽  
...  
Keyword(s):  
Proteasome Inhibitor ◽  
Enzyme Inhibitor ◽  
Mixed Lineage Leukemia ◽  
Deubiquitinating Enzyme ◽  
Cyclin A1 ◽  
Inhibitor Tolerance

scholarly journals Deubiquitinating Enzyme Inhibitor Alleviates Cyclin A1-mediated Proteasome Inhibitor Tolerance in Mixed-lineage Leukemia

2020 ◽  
Author(s):  
Maolin Ge ◽  
Qiongyu Xu ◽  
Ting Kang ◽  
Dan Li ◽  
Ruiheng Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Proteasome Inhibitor ◽  
Enzyme Inhibitor ◽  
Mixed Lineage Leukemia ◽  
Deubiquitinating Enzyme ◽  
Protein Loss ◽  
Cyclin A1 ◽  
Inhibitor Tolerance

Abstract Background: Drug resistance is a significant obstacle to effective cancer treatment. Drug resistance develops from initially reversible drug-tolerant cancer cells, which offers therapeutic opportunities to impede cancer relapse. The mechanisms of resistance to proteasome inhibitor (PI) therapy have been investigated intensively; however, the ways by which drug-tolerant cancer cells orchestrate their adaptive responses to drug challenges remains largely unknown. Methods: RNA sequencing and bioinformatics analyses were employed to assess dysregulated cell cycle genes. Chromatin immunoprecipitation assays were performed to evaluate the involvement of MLL in cyclin A1 transcriptional activity. Cell cycle assays, cell viability assays, immunoblots, and apoptosis assays were performed to evaluate the dependency of cyclin A1 during tolerance acquisition.Results: Here, we demonstrated that cyclin A1 suppression elicited the development of transient PI tolerance in mixed-lineage leukemia (MLL) cells. This adaptive process involved reversible down-regulation of cyclin A1, which promoted PI resistance through cell cycle arrest. PI-tolerant MLL cells acquired cyclin A1 dependency, regulated directly by MLL protein. Loss of cyclin A1 function resulted in the emergence of drug tolerance, which was associated with patient relapse and reduced survival. Combination treatment with PI and deubiquitinating enzyme (DUB) inhibitors overcame this drug resistance by restoring cyclin A1 expression through chromatin crosstalk between histone H2B monoubiquitination and MLL-mediated histone H3 lysine 4 methylation. Conclusion: These results reveal the importance of cyclin A1-engaged cell cycle regulation in PI resistance in MLL cells, and suggest that cell cycle re-entry by DUB inhibitors may represent a promising epigenetic therapeutic strategy to prevent acquired drug resistance.

scholarly journals The Deubiquitinating Enzyme Inhibitor PR-619 is a Potent DNA Topoisomerase II Poison

2019 ◽  
Vol 96 (5) ◽  
pp. 562-572
Author(s):  
Ian G. Cowell ◽  
Elise M. Ling ◽  
Rebecca L. Swan ◽  
Matilda L.W. Brooks ◽  
Caroline A. Austin
Keyword(s):  
Topoisomerase Ii ◽  
Enzyme Inhibitor ◽  
Deubiquitinating Enzyme ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase

scholarly journals Diarylcarbonates are a new class of deubiquitinating enzyme inhibitor

2019 ◽  
Vol 29 (2) ◽  
pp. 204-211 ◽  
Author(s):  
Marcus J.C. Long ◽  
Ann P. Lawson ◽  
Rick Baggio ◽  
Yu Qian ◽  
Lior Rozhansky ◽  
...  
Keyword(s):  
Enzyme Inhibitor ◽  
Deubiquitinating Enzyme ◽  
New Class

scholarly journals The Papain-Like Protease from the Severe Acute Respiratory Syndrome Coronavirus Is a Deubiquitinating Enzyme

2005 ◽  
Vol 79 (24) ◽  
pp. 15199-15208 ◽  
Author(s):  
Holger A. Lindner ◽  
Nasser Fotouhi-Ardakani ◽  
Viktoria Lytvyn ◽  
Paule Lachance ◽  
Traian Sulea ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Enzyme Inhibitor ◽  
Bond Cleavage ◽  
Catalytic Efficiency ◽  
Deubiquitinating Enzyme ◽  
C Terminus ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Complex Structural

ABSTRACT The severe acute respiratory syndrome coronavirus papain-like protease (SARS-CoV PLpro) is involved in the processing of the viral polyprotein and, thereby, contributes to the biogenesis of the virus replication complex. Structural bioinformatics has revealed a relationship for the SARS-CoV PLpro to herpesvirus-associated ubiquitin-specific protease (HAUSP), a ubiquitin-specific protease, indicating potential deubiquitinating activity in addition to its function in polyprotein processing (T. Sulea, H. A. Lindner, E. O. Purisima, and R. Menard, J. Virol. 79:4550-4551, 2005). In order to confirm this prediction, we overexpressed and purified SARS-CoV PLpro (amino acids [aa]1507 to 1858) from Escherichia coli. The purified enzyme hydrolyzed ubiquitin-7-amino-4-methylcoumarin (Ub-AMC), a general deubiquitinating enzyme substrate, with a catalytic efficiency of 13,100 M−1s−1, 220-fold more efficiently than the small synthetic peptide substrate Z-LRGG-AMC, which incorporates the C-terminal four residues of ubiquitin. In addition, SARS-CoV PLpro was inhibited by the specific deubiquitinating enzyme inhibitor ubiquitin aldehyde, with an inhibition constant of 210 nM. The purified SARS-CoV PLpro disassembles branched polyubiquitin chains with lengths of two to seven (Ub2-7) or four (Ub4) units, which involves isopeptide bond cleavage. SARS-CoV PLpro processing activity was also detected against a protein fused to the C terminus of the ubiquitin-like modifier ISG15, both in vitro using the purified enzyme and in HeLa cells by coexpression with SARS-CoV PLpro (aa 1198 to 2009). These results clearly establish that SARS-CoV PLpro is a deubiquitinating enzyme, thereby confirming our earlier prediction. This unexpected activity for a coronavirus papain-like protease suggests a novel viral strategy to modulate the host cell ubiquitination machinery to its advantage.

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