A novel combination therapy targeting ubiquitin-specific protease 5 in MYCN-driven neuroblastoma

Autor: Owen Tan, Sonya M. Diakiw, Patrick Y. Kim, Janith A. Seneviratne, Chelsea Mayoh, Olle Sangfelt, Naresh Kumar, Daniel R. Carter, Rituparna Mittra, Ane Kleynhans, Michelle Haber, Belamy B. Cheung, Zsuzsanna Nagy, Jessica K Holien, Murray D. Norris, Aldwin Suryano, Iris Poh Ling Wong, Bing Liu, Olivia C. Ciampa, Hassina Massudi, Mukesh Raipuria, Andrew Gong, Tao Liu, Michael W. Parker, Shizhen Zhu, Greg M. Arndt, Glenn M. Marshall, Satyanarayana Gadde
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Cancer Research
Carcinogenesis
Drug Evaluation
Preclinical
Apoptosis
medicine.disease_cause
Animals
Genetically Modified
chemistry.chemical_compound
Mice
Neuroblastoma
0302 clinical medicine
Ubiquitin
Cytotoxic T cell
Zebrafish
N-Myc Proto-Oncogene Protein
Vorinostat
biology
High-throughput screening
1103 Clinical Sciences
1112 Oncology and Carcinogenesis
Gene Expression Regulation
Neoplastic
030220 oncology & carcinogenesis
Heterografts
Ubiquitin-Specific Proteases
Cell Survival
Article
Paediatric cancer
Small Molecule Libraries
03 medical and health sciences
Target identification
Genetics
medicine
Animals
Humans
Oncology & Carcinogenesis
Viability assay
Molecular Biology
neoplasms
Cell Proliferation
Hydroxamic acid
Zebrafish Proteins
medicine.disease
Histone Deacetylase Inhibitors
030104 developmental biology
chemistry
biology.protein
Cancer research
Histone deacetylase
Zdroj: Oncogene
ISSN: 1476-5594
0950-9232
Popis: Histone deacetylase (HDAC) inhibitors are effective in MYCN-driven cancers, because of a unique need for HDAC recruitment by the MYCN oncogenic signal. However, HDAC inhibitors are much more effective in combination with other anti-cancer agents. To identify novel compounds which act synergistically with HDAC inhibitor, such as suberanoyl hydroxamic acid (SAHA), we performed a cell-based, high-throughput drug screen of 10,560 small molecule compounds from a drug-like diversity library and identified a small molecule compound (SE486-11) which synergistically enhanced the cytotoxic effects of SAHA. Effects of drug combinations on cell viability, proliferation, apoptosis and colony forming were assessed in a panel of neuroblastoma cell lines. Treatment with SAHA and SE486-11 increased MYCN ubiquitination and degradation, and markedly inhibited tumorigenesis in neuroblastoma xenografts, and, MYCN transgenic zebrafish and mice. The combination reduced ubiquitin-specific protease 5 (USP5) levels and increased unanchored polyubiquitin chains. Overexpression of USP5 rescued neuroblastoma cells from the cytopathic effects of the combination and reduced unanchored polyubiquitin, suggesting USP5 is a therapeutic target of the combination. SAHA and SE486-11 directly bound to USP5 and the drug combination exhibited a 100-fold higher binding to USP5 than individual drugs alone in microscale thermophoresis assays. MYCN bound to the USP5 promoter and induced USP5 gene expression suggesting that USP5 and MYCN expression created a forward positive feedback loop in neuroblastoma cells. Thus, USP5 acts as an oncogenic cofactor with MYCN in neuroblastoma and the novel combination of HDAC inhibitor with SE486-11 represents a novel therapeutic approach for the treatment of MYCN-driven neuroblastoma.
Databáze: OpenAIRE
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