HAUSP deubiquitinates and stabilizes N-Myc in neuroblastoma.
The MYCN proto-oncogene is amplified in a number of advanced-stage human tumors, such as neuroblastomas. Similar to other members of the MYC family of oncoproteins, MYCN (also known as N-Myc) is a transcription factor, and its stability and activity are tightly controlled by ubiquitination-dependent proteasome degradation. Although numerous studies have demonstrated that N-Myc is a driver of neuroblastoma tumorigenesis, therapies that directly suppress N-Myc activity in human tumors are limited. Here we have identified ubiquitin-specific protease 7 (USP7; also known as HAUSP) as a regulator of N-Myc function in neuroblastoma. HAUSP interacts with N-Myc, and HAUSP expression induces deubiquitination and subsequent stabilization of N-Myc. Conversely, RNA interference (RNAi)-mediated knockdown of USP7 in neuroblastoma cancer cell lines, or genetic ablation of Usp7 in the mouse brain, destabilizes N-Myc, which leads to inhibition of N-Myc function. Notably, HAUSP is more abundant in patients with neuroblastoma who have poorer prognosis, and HAUSP expression substantially correlates with N-Myc transcriptional activity. Furthermore, small-molecule inhibitors of HAUSP's deubiquitinase activity markedly suppress the growth of MYCN-amplified human neuroblastoma cell lines in xenograft mouse models. Taken together, our findings demonstrate a crucial role of HAUSP in regulating N-Myc function in vivo and suggest that HAUSP inhibition is a potential therapy for MYCN-amplified tumors.
Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, New York, USA.|Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Omid
O
Tavana
Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, New York, USA.|Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Dawei
D
Li
Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, New York, USA.|Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Chao
C
Dai
Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, New York, USA.|Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York, USA.|Department of Systems Biology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.|Center for Computational Biology and Bioinformatics, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Gonzalo
G
Lopez
Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York, USA.|Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Debarshi
D
Banerjee
Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, New York, USA.|Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Ning
N
Kon
Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing, China.|State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
Chao
C
Chen
Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, New York, USA.|Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York, USA.|Department of Systems Biology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.|Center for Computational Biology and Bioinformatics, College of Physicians and Surgeons, Columbia University, New York, New York, USA.|Department of Biomedical Informatics, Biochemistry and Molecular Biophysics, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Andrea
A
Califano
Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York, USA.|Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Darrell J
DJ
Yamashiro
Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing, China.|State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
Hongbin
H
Sun
Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, New York, USA.|Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York, USA.|Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Wei
W
Gu
D000818:Animals; D015153:Blotting, Western; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D000071447:N-Myc Proto-Oncogene Protein / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D000076084:Ubiquitin-Specific Peptidase 7; D064570:Ubiquitin-Specific Proteases / Q000235:genetics / Q000378:metabolism*
C000715470:MAS1 protein, human; D000071447:N-Myc Proto-Oncogene Protein; D000090063:Proto-Oncogene Mas; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7; D064570:Ubiquitin-Specific Proteases; C579190:Usp7 protein, mouse