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 |
Externí odkaz: |