TY - JOUR
T1 - DROSHA Regulates Mesenchymal Gene Expression in Wilms Tumor
AU - Tiburcio, Patricia D.B.
AU - Desai, Kavita
AU - Kim, Jiwoong
AU - Zhou, Qinbo
AU - Guo, Lei
AU - Xiao, Xue
AU - Zhou, Li
AU - Yuksel, Aysen
AU - Catchpoole, Daniel R.
AU - Amatruda, James F.
AU - Xu, Lin
AU - Chen, Kenneth S.
N1 - Publisher Copyright:
©2024 American Association for Cancer Research.
PY - 2024/8/1
Y1 - 2024/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85200524418&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-23-0930
DO - 10.1158/1541-7786.MCR-23-0930
M3 - Article
C2 - 38647377
AN - SCOPUS:85200524418
SN - 1541-7786
VL - 22
SP - 711
EP - 720
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 8
ER -