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Cancer Cell. 2019 Jan 14;35(1):46-63.e10. doi: 10.1016/j.ccell.2018.11.008. Epub 2018 Dec 20.

p62/SQSTM1 Fuels Melanoma Progression by Opposing mRNA Decay of a Selective Set of Pro-metastatic Factors.

Author information

1
Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
2
Hospital Universitario 12 de Octubre, Instituto Investigación i+12, Medical School, Universidad Complutense, Madrid, Spain.
3
Bioinformatics Unit, CNIO, Madrid 28029, Spain.
4
Proteomics Core Unit, CNIO, Madrid 28029, Spain.
5
Confocal Microscopy Unit, CNIO, Madrid 28029, Spain.
6
Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
7
Hospital Universitario 12 de Octubre, Instituto Investigación i+12, Medical School, Universidad Complutense, Madrid, Spain. Electronic address: jrperalto@salud.madrid.org.
8
Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain. Electronic address: msoengas@cnio.es.

Abstract

Modulators of mRNA stability are not well understood in melanoma, an aggressive tumor with complex changes in the transcriptome. Here we report the ability of p62/SQSTM1 to extend mRNA half-life of a spectrum of pro-metastatic factors. These include FERMT2 and other transcripts with no previous links to melanoma. Transcriptomic, proteomic, and interactomic analyses, combined with validation in clinical biopsies and mouse models, identified a selected set of RNA-binding proteins (RBPs) recruited by p62, with IGF2BP1 as a key partner. This p62-RBP interaction distinguishes melanoma from other tumors where p62 controls autophagy or oxidative stress. The relevance of these data is emphasized by follow-up analyses of patient prognosis revealing p62 and FERMT2 as adverse determinants of disease-free survival.

KEYWORDS:

FERMT2; IGF2BP1; RNA-binding proteins; gene networks; genetically engineered mouse models; interactomics; melanoma; metastasis; p62/SQSTM1; prognostic indicators; proteomics; transcriptomics

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