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

Cheung, BB; Kleynhans, A; Mittra, R; Kim, PY; Holien, JK; Nagy, Z; Ciampa, OC; Seneviratne, JA; Mayoh, C; Raipuria, M; Gadde, S; Massudi, H; Wong, IPL; Tan, O; Gong, A; Suryano, A; Diakiw, SM; Liu, B; Arndt, GM; Liu, T; Kumar, N; Sangfelt, O; Zhu, S; Norris, MD; Haber, M; Carter, DR; Parker, MW; Marshall, GM

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

Cheung, BB Kleynhans, A Mittra, R Kim, PY Holien, JK Nagy, Z Ciampa, OC Seneviratne, JA Mayoh, C Raipuria, M Gadde, S Massudi, H Wong, IPL Tan, O Gong, A Suryano, A Diakiw, SM Liu, B Arndt, GM Liu, T Kumar, N Sangfelt, O Zhu, S Norris, MD Haber, M Carter, DR Parker, MW Marshall, GM

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Publisher:: Springer Nature [academic journals on nature.com]
Publication Type:: Journal Article
Citation:: Oncogene, 2021, 40, (13), pp. 2367-2381
Issue Date:: 2021-03-03

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Field	Value	Language
dc.contributor.author	Cheung, BB
dc.contributor.author	Kleynhans, A
dc.contributor.author	Mittra, R
dc.contributor.author	Kim, PY
dc.contributor.author	Holien, JK
dc.contributor.author	Nagy, Z
dc.contributor.author	Ciampa, OC
dc.contributor.author	Seneviratne, JA
dc.contributor.author	Mayoh, C
dc.contributor.author	Raipuria, M
dc.contributor.author	Gadde, S
dc.contributor.author	Massudi, H
dc.contributor.author	Wong, IPL
dc.contributor.author	Tan, O
dc.contributor.author	Gong, A
dc.contributor.author	Suryano, A
dc.contributor.author	Diakiw, SM
dc.contributor.author	Liu, B
dc.contributor.author	Arndt, GM
dc.contributor.author	Liu, T
dc.contributor.author	Kumar, N
dc.contributor.author	Sangfelt, O
dc.contributor.author	Zhu, S
dc.contributor.author	Norris, MD
dc.contributor.author	Haber, M
dc.contributor.author	Carter, DR
dc.contributor.author	Parker, MW
dc.contributor.author	Marshall, GM
dc.date.accessioned	2022-02-25T02:54:32Z
dc.date.available	2021-02-11
dc.date.available	2022-02-25T02:54:32Z
dc.date.issued	2021-03-03
dc.identifier.citation	Oncogene, 2021, 40, (13), pp. 2367-2381
dc.identifier.issn	0950-9232
dc.identifier.issn	1476-5594
dc.identifier.uri	http://hdl.handle.net/10453/154845
dc.description.abstract	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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Springer Nature [academic journals on nature.com]
dc.relation.ispartof	Oncogene
dc.relation.isbasedon	10.1038/s41388-021-01712-w
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	1103 Clinical Sciences, 1112 Oncology and Carcinogenesis
dc.subject.classification	Oncology & Carcinogenesis
dc.subject.mesh	Animals
dc.subject.mesh	Animals, Genetically Modified
dc.subject.mesh	Apoptosis
dc.subject.mesh	Carcinogenesis
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	Cell Survival
dc.subject.mesh	Drug Evaluation, Preclinical
dc.subject.mesh	Gene Expression Regulation, Neoplastic
dc.subject.mesh	Heterografts
dc.subject.mesh	Histone Deacetylase Inhibitors
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	N-Myc Proto-Oncogene Protein
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Small Molecule Libraries
dc.subject.mesh	Ubiquitin-Specific Proteases
dc.subject.mesh	Vorinostat
dc.subject.mesh	Zebrafish
dc.subject.mesh	Zebrafish Proteins
dc.subject.mesh	Animals
dc.subject.mesh	Animals, Genetically Modified
dc.subject.mesh	Zebrafish
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Zebrafish Proteins
dc.subject.mesh	Drug Evaluation, Preclinical
dc.subject.mesh	Apoptosis
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	Cell Survival
dc.subject.mesh	Gene Expression Regulation, Neoplastic
dc.subject.mesh	Small Molecule Libraries
dc.subject.mesh	Histone Deacetylase Inhibitors
dc.subject.mesh	Ubiquitin-Specific Proteases
dc.subject.mesh	Carcinogenesis
dc.subject.mesh	Heterografts
dc.subject.mesh	N-Myc Proto-Oncogene Protein
dc.subject.mesh	Vorinostat
dc.title	A novel combination therapy targeting ubiquitin-specific protease 5 in MYCN-driven neuroblastoma
dc.type	Journal Article
utslib.citation.volume	40
utslib.location.activity	England
utslib.for	1103 Clinical Sciences
utslib.for	1112 Oncology and Carcinogenesis
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	/University of Technology Sydney/Centre for Health Technologies (CHT)
utslib.copyright.status	open_access	*
pubs.consider-herdc	false
dc.date.updated	2022-02-25T02:54:27Z
pubs.issue	13
pubs.publication-status	Published
pubs.volume	40
utslib.citation.issue	13

Abstract:

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.

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http://hdl.handle.net/10453/154845