DROSHA Regulates Mesenchymal Gene Expression in Wilms Tumor

Patricia D.B. Tiburcio, Kavita Desai, Jiwoong Kim, Qinbo Zhou, Lei Guo, Xue Xiao, Li Zhou, Aysen Yuksel, Daniel R. Catchpoole, James F. Amatruda, Lin Xu, Kenneth S. Chen

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)711-720
Number of pages10
JournalMolecular Cancer Research
Volume22
Issue number8
DOIs
StatePublished - 1 Aug 2024
Externally publishedYes

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