Abstract
Inhibition of Mdm2 function is a validated approach to restore p53 activity for cancer therapy; nevertheless, inhibitors of Mdm2 such as Nutlin-3 have certain limitations, suggesting that additional targets in this pathway need to be further elucidated. Our finding that the Herpesvirus-Associated Ubiquitin-Specific Protease (HAUSP, also called USP7) interacts with the p53/Mdm2 protein complex, was one of the first examples that deubiquitinases (DUBs) exhibit a specific role in regulating protein stability. Here, we show that inhibitors of HAUSP and Nutlin-3 can synergistically activate p53 function and induce p53-dependent apoptosis in human cancer cells. Notably, HAUSP can also target the N-Myc oncoprotein in a p53-independent manner. Moreover, newly synthesized HAUSP inhibitors are more potent than the commercially available inhibitors to suppress N-Myc activities in p53 mutant cells for growth suppression. Taken together, our study demonstrates the utility of HAUSP inhibitors to target cancers in both a p53-depdentent and -independent manner.
Keywords:
HAUSP; N-Myc; USP7; cancer; p53 activation.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Antineoplastic Agents / pharmacology*
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Apoptosis
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Cell Line, Tumor
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Gene Expression Regulation, Neoplastic*
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HCT116 Cells
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Humans
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Imidazoles / pharmacology
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Indenes / pharmacology
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Molecular Targeted Therapy
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N-Myc Proto-Oncogene Protein / genetics
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N-Myc Proto-Oncogene Protein / metabolism
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Neurons / drug effects
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Neurons / enzymology
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Neurons / pathology
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Piperazines / pharmacology
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Protease Inhibitors / pharmacology*
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Protein Stability
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Proto-Oncogene Proteins c-mdm2 / genetics*
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Proto-Oncogene Proteins c-mdm2 / metabolism
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Pyrazines / pharmacology
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Signal Transduction
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Thiophenes / pharmacology
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Tumor Suppressor Protein p53 / deficiency
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Tumor Suppressor Protein p53 / genetics*
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Ubiquitin-Specific Peptidase 7 / antagonists & inhibitors
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Ubiquitin-Specific Peptidase 7 / genetics*
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Ubiquitin-Specific Peptidase 7 / metabolism
Substances
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Antineoplastic Agents
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HBX 41,108
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Imidazoles
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Indenes
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MYCN protein, human
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N-Myc Proto-Oncogene Protein
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P5091
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Piperazines
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Protease Inhibitors
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Pyrazines
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RNA, Small Interfering
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TP53 protein, human
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Thiophenes
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Tumor Suppressor Protein p53
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nutlin 3
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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USP7 protein, human
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Ubiquitin-Specific Peptidase 7