An ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability

Nagy, Z; Seneviratne, JA; Kanikevich, M; Chang, W; Mayoh, C; Venkat, P; Du, Y; Jiang, C; Salib, A; Koach, J; Carter, DR; Mittra, R; Liu, T; Parker, MW; Cheung, BB; Marshall, GM

An ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability

Nagy, Z Seneviratne, JA Kanikevich, M Chang, W Mayoh, C Venkat, P Du, Y Jiang, C Salib, A Koach, J Carter, DR Mittra, R Liu, T Parker, MW Cheung, BB Marshall, GM

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Publisher:: Nature Research
Publication Type:: Journal Article
Citation:: Nature Communications, 2021, 12, (1), pp. 1-20
Issue Date:: 2021-03-25

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Field	Value	Language
dc.contributor.author	Nagy, Z
dc.contributor.author	Seneviratne, JA
dc.contributor.author	Kanikevich, M
dc.contributor.author	Chang, W
dc.contributor.author	Mayoh, C
dc.contributor.author	Venkat, P
dc.contributor.author	Du, Y
dc.contributor.author	Jiang, C
dc.contributor.author	Salib, A
dc.contributor.author	Koach, J
dc.contributor.author	Carter, DR
dc.contributor.author	Mittra, R
dc.contributor.author	Liu, T
dc.contributor.author	Parker, MW
dc.contributor.author	Cheung, BB
dc.contributor.author	Marshall, GM
dc.date.accessioned	2022-03-09T23:50:40Z
dc.date.available	2021-02-23
dc.date.available	2022-03-09T23:50:40Z
dc.date.issued	2021-03-25
dc.identifier.citation	Nature Communications, 2021, 12, (1), pp. 1-20
dc.identifier.issn	2041-1723
dc.identifier.issn	2041-1723
dc.identifier.uri	http://hdl.handle.net/10453/155123
dc.description.abstract	To achieve the very high oncoprotein levels required to drive the malignant state cancer cells utilise the ubiquitin proteasome system to upregulate transcription factor levels. Here our analyses identify ALYREF, expressed from the most common genetic copy number variation in neuroblastoma, chromosome 17q21-ter gain as a key regulator of MYCN protein turnover. We show strong co-operativity between ALYREF and MYCN from transgenic models of neuroblastoma in vitro and in vivo. The two proteins form a nuclear coactivator complex which stimulates transcription of the ubiquitin specific peptidase 3, USP3. We show that increased USP3 levels reduce K-48- and K-63-linked ubiquitination of MYCN, thus driving up MYCN protein stability. In the MYCN-ALYREF-USP3 signal, ALYREF is required for MYCN effects on the malignant phenotype and that of USP3 on MYCN stability. This data defines a MYCN oncoprotein dependency state which provides a rationale for future pharmacological studies.
dc.format	Electronic
dc.language	eng
dc.publisher	Nature Research
dc.relation.ispartof	Nature Communications
dc.relation.isbasedon	10.1038/s41467-021-22143-x
dc.rights	info:eu-repo/semantics/openAccess
dc.subject.mesh	Animals
dc.subject.mesh	Carcinogenesis
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Cell Survival
dc.subject.mesh	Chromosomes, Human, Pair 17
dc.subject.mesh	DNA Copy Number Variations
dc.subject.mesh	HEK293 Cells
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	N-Myc Proto-Oncogene Protein
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Nuclear Proteins
dc.subject.mesh	Prognosis
dc.subject.mesh	RNA Interference
dc.subject.mesh	RNA, Small Interfering
dc.subject.mesh	RNA-Binding Proteins
dc.subject.mesh	Transcription Factors
dc.subject.mesh	Transcription, Genetic
dc.subject.mesh	Transcriptional Activation
dc.subject.mesh	Ubiquitin-Specific Proteases
dc.subject.mesh	Ubiquitination
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Chromosomes, Human, Pair 17
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	RNA-Binding Proteins
dc.subject.mesh	Nuclear Proteins
dc.subject.mesh	Transcription Factors
dc.subject.mesh	RNA, Small Interfering
dc.subject.mesh	Prognosis
dc.subject.mesh	Cell Survival
dc.subject.mesh	Transcription, Genetic
dc.subject.mesh	RNA Interference
dc.subject.mesh	Ubiquitination
dc.subject.mesh	Transcriptional Activation
dc.subject.mesh	DNA Copy Number Variations
dc.subject.mesh	HEK293 Cells
dc.subject.mesh	Ubiquitin-Specific Proteases
dc.subject.mesh	Carcinogenesis
dc.subject.mesh	N-Myc Proto-Oncogene Protein
dc.title	An ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability
dc.type	Journal Article
utslib.citation.volume	12
utslib.location.activity	England
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	2022-03-09T23:50:33Z
pubs.issue	1
pubs.publication-status	Published
pubs.volume	12
utslib.citation.issue	1

Abstract:

To achieve the very high oncoprotein levels required to drive the malignant state cancer cells utilise the ubiquitin proteasome system to upregulate transcription factor levels. Here our analyses identify ALYREF, expressed from the most common genetic copy number variation in neuroblastoma, chromosome 17q21-ter gain as a key regulator of MYCN protein turnover. We show strong co-operativity between ALYREF and MYCN from transgenic models of neuroblastoma in vitro and in vivo. The two proteins form a nuclear coactivator complex which stimulates transcription of the ubiquitin specific peptidase 3, USP3. We show that increased USP3 levels reduce K-48- and K-63-linked ubiquitination of MYCN, thus driving up MYCN protein stability. In the MYCN-ALYREF-USP3 signal, ALYREF is required for MYCN effects on the malignant phenotype and that of USP3 on MYCN stability. This data defines a MYCN oncoprotein dependency state which provides a rationale for future pharmacological studies.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/155123