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MicroRNA-424 impairs ubiquitination to activate STAT3 and promote prostate tumor progression
Cecilia Dallavalle, … , Carlo V. Catapano, Giuseppina M. Carbone
Cecilia Dallavalle, … , Carlo V. Catapano, Giuseppina M. Carbone
Published November 7, 2016
Citation Information: J Clin Invest. 2016;126(12):4585-4602. https://doi.org/10.1172/JCI86505.
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Research Article Oncology Article has an altmetric score of 2

MicroRNA-424 impairs ubiquitination to activate STAT3 and promote prostate tumor progression

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Abstract

Mutations and deletions in components of ubiquitin ligase complexes that lead to alterations in protein turnover are important mechanisms in driving tumorigenesis. Here we describe an alternative mechanism involving upregulation of the microRNA miR-424 that leads to impaired ubiquitination and degradation of oncogenic transcription factors in prostate cancers. We found that miR-424 targets the E3 ubiquitin ligase COP1 and identified STAT3 as a key substrate of COP1 in promoting tumorigenic and cancer stem-like properties in prostate epithelial cells. Altered protein turnover due to impaired COP1 function led to accumulation and enhanced basal and cytokine-induced activity of STAT3. We further determined that loss of the ETS factor ESE3/EHF is the initial event that triggers the deregulation of the miR-424/COP1/STAT3 axis. COP1 silencing and STAT3 activation were effectively reverted by blocking of miR-424, suggesting a possible strategy to attack this key node of tumorigenesis in ESE3/EHF–deficient tumors. These results establish miR-424 as an oncogenic effector linked to noncanonical activation of STAT3 and as a potential therapeutic target.

Authors

Cecilia Dallavalle, Domenico Albino, Gianluca Civenni, Jessica Merulla, Paola Ostano, Maurizia Mello-Grand, Simona Rossi, Marco Losa, Gioacchino D’Ambrosio, Fausto Sessa, George N. Thalmann, Ramon Garcia-Escudero, Andrea Zitella, Giovanna Chiorino, Carlo V. Catapano, Giuseppina M. Carbone

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Figure 1

miR-424 is elevated in prostate tumors and is associated with EMT and stem cell–like features.

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miR-424 is elevated in prostate tumors and is associated with EMT and st...
(A) Unsupervised hierarchical clustering (UHC) of primary prostate tumors from the Biella data set according to their miRNA profile. ESE3lo tumors (blue rectangles) cluster together and have similar miRNA profile. (B) miR-424 log2 intensity levels evaluated by microarray (left) and relative expression levels evaluated by qRT-PCR (right) in prostate tumors. (C) miR-424 level evaluated by qRT-PCR in indicated prostate cell lines. The results were normalized to RNU6 internal control. (D) Prostate samples divided according to miR-424 expression in 2 independent primary prostate tumor data sets, The Cancer Genome Atlas (TCGA) project and the in-house Biella data set (see Methods for details). (E) Gene set enrichment analysis (GSEA) comparing miR-424hi with miR-424lo prostate tumors in the 2 indicated microarray data sets (total = 545), using the indicated stem cell–like and EMT gene signatures. (F) Venn diagram crossing genes upregulated in miR-424hi signatures extracted from Biella and TCGA data sets and showing a significantly high convergence (P < 0.00001). (G) Functional analysis of miR-424hi signatures in Biella and TCGA data sets using ENCODE pathway analysis tools. Signatures were extracted by comparison of miR-424hi versus miR-424lo samples. See Methods for experimental details.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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