DROSHA Regulates Mesenchymal Gene Expression in Wilms Tumor.

Tiburcio, PDB; Desai, K; Kim, J; Zhou, Q; Guo, L; Xiao, X; Zhou, L; Yuksel, A; Catchpoole, DR; Amatruda, JF; Xu, L; Chen, KS

DROSHA Regulates Mesenchymal Gene Expression in Wilms Tumor.

Tiburcio, PDB Desai, K Kim, J Zhou, Q Guo, L Xiao, X Zhou, L Yuksel, A Catchpoole, DR Amatruda, JF Xu, L Chen, KS

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Publisher:: AMER ASSOC CANCER RESEARCH
Publication Type:: Journal Article
Citation:: Mol Cancer Res, 2024, 22, (8), pp. 711-720
Issue Date:: 2024-08-02

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Field	Value	Language
dc.contributor.author	Tiburcio, PDB
dc.contributor.author	Desai, K
dc.contributor.author	Kim, J
dc.contributor.author	Zhou, Q
dc.contributor.author	Guo, L
dc.contributor.author	Xiao, X
dc.contributor.author	Zhou, L
dc.contributor.author	Yuksel, A
dc.contributor.author	Catchpoole, DR
dc.contributor.author	Amatruda, JF
dc.contributor.author	Xu, L
dc.contributor.author	Chen, KS
dc.date.accessioned	2024-11-04T01:18:44Z
dc.date.available	2024-04-08
dc.date.available	2024-11-04T01:18:44Z
dc.date.issued	2024-08-02
dc.identifier.citation	Mol Cancer Res, 2024, 22, (8), pp. 711-720
dc.identifier.issn	1541-7786
dc.identifier.issn	1557-3125
dc.identifier.uri	http://hdl.handle.net/10453/181688
dc.description.abstract	Wilms tumor, the most common pediatric kidney cancer, resembles embryonic renal progenitors. Currently, there are no ways to therapeutically target Wilms tumor driver mutations, such as in the microRNA processing gene DROSHA. In this study, we used a "multiomics" approach to define the effects of DROSHA mutation in Wilms tumor. We categorized Wilms tumor mutations into four mutational subclasses with unique transcriptional effects: microRNA processing, MYCN activation, chromatin remodeling, and kidney developmental factors. In particular, we find that DROSHA mutations are correlated with de-repressing microRNA target genes that regulate differentiation and proliferation and a self-renewing, mesenchymal state. We model these findings by inhibiting DROSHA expression in a Wilms tumor cell line, which led to upregulation of the cell cycle regulator cyclin D2 (CCND2). Furthermore, we observed that DROSHA mutations in Wilms tumor and DROSHA silencing in vitro were associated with a mesenchymal state with aberrations in redox metabolism. Accordingly, we demonstrate that Wilms tumor cells lacking microRNAs are sensitized to ferroptotic cell death through inhibition of glutathione peroxidase 4, the enzyme that detoxifies lipid peroxides. Implications: This study reveals genotype-transcriptome relationships in Wilms tumor and points to ferroptosis as a potentially therapeutic vulnerability in one subset of Wilms tumor.
dc.format	Print
dc.language	eng
dc.publisher	AMER ASSOC CANCER RESEARCH
dc.relation.ispartof	Mol Cancer Res
dc.relation.isbasedon	10.1158/1541-7786.MCR-23-0930
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	1112 Oncology and Carcinogenesis
dc.subject.classification	Developmental Biology
dc.subject.classification	Oncology & Carcinogenesis
dc.subject.classification	3101 Biochemistry and cell biology
dc.subject.classification	3211 Oncology and carcinogenesis
dc.subject.mesh	Humans
dc.subject.mesh	Wilms Tumor
dc.subject.mesh	Ribonuclease III
dc.subject.mesh	Kidney Neoplasms
dc.subject.mesh	Gene Expression Regulation, Neoplastic
dc.subject.mesh	Mutation
dc.subject.mesh	MicroRNAs
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Humans
dc.subject.mesh	Kidney Neoplasms
dc.subject.mesh	Ribonuclease III
dc.subject.mesh	MicroRNAs
dc.subject.mesh	Gene Expression Regulation, Neoplastic
dc.subject.mesh	Mutation
dc.subject.mesh	Wilms Tumor
dc.subject.mesh	Humans
dc.subject.mesh	Wilms Tumor
dc.subject.mesh	Ribonuclease III
dc.subject.mesh	Kidney Neoplasms
dc.subject.mesh	Gene Expression Regulation, Neoplastic
dc.subject.mesh	Mutation
dc.subject.mesh	MicroRNAs
dc.subject.mesh	Cell Line, Tumor
dc.title	DROSHA Regulates Mesenchymal Gene Expression in Wilms Tumor.
dc.type	Journal Article
utslib.citation.volume	22
utslib.location.activity	United States
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/Faculty of Engineering and Information Technology/School of Computer Science
pubs.organisational-group	University of Technology Sydney/UTS Groups
pubs.organisational-group	University of Technology Sydney/UTS Groups/Australian Artificial Intelligence Institute (AAII)
pubs.organisational-group	University of Technology Sydney/UTS Groups/Digital, Virtual and AI in Health Collaborative (DVAIHC)
pubs.organisational-group	University of Technology Sydney/UTS Groups/INSIGHT: Institute for Innovative Solutions for Well-being and Health
pubs.organisational-group	University of Technology Sydney/UTS Groups/Australian Artificial Intelligence Institute (AAII)/Australian Artificial Intelligence Institute (AAII) Associate Member
pubs.organisational-group	University of Technology Sydney/UTS Groups/The Trustworthy Digital Society
utslib.copyright.status	closed_access	*
dc.date.updated	2024-11-04T01:18:42Z
pubs.issue	8
pubs.publication-status	Published
pubs.volume	22
utslib.citation.issue	8

Abstract:

Wilms tumor, the most common pediatric kidney cancer, resembles embryonic renal progenitors. Currently, there are no ways to therapeutically target Wilms tumor driver mutations, such as in the microRNA processing gene DROSHA. In this study, we used a "multiomics" approach to define the effects of DROSHA mutation in Wilms tumor. We categorized Wilms tumor mutations into four mutational subclasses with unique transcriptional effects: microRNA processing, MYCN activation, chromatin remodeling, and kidney developmental factors. In particular, we find that DROSHA mutations are correlated with de-repressing microRNA target genes that regulate differentiation and proliferation and a self-renewing, mesenchymal state. We model these findings by inhibiting DROSHA expression in a Wilms tumor cell line, which led to upregulation of the cell cycle regulator cyclin D2 (CCND2). Furthermore, we observed that DROSHA mutations in Wilms tumor and DROSHA silencing in vitro were associated with a mesenchymal state with aberrations in redox metabolism. Accordingly, we demonstrate that Wilms tumor cells lacking microRNAs are sensitized to ferroptotic cell death through inhibition of glutathione peroxidase 4, the enzyme that detoxifies lipid peroxides. Implications: This study reveals genotype-transcriptome relationships in Wilms tumor and points to ferroptosis as a potentially therapeutic vulnerability in one subset of Wilms tumor.

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

http://hdl.handle.net/10453/181688