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

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. [Display omitted] •p62 controls gene signatures upregulated in metastatic melanomas•RNA-binding proteins (RBPs) are enriched within the p62 interactome•p62 stabilizes the mRNAs of FERMT2 and other pro-metastatic factors via IGF2BP1•Protein levels of p62 and FERMT2 in melanomas correlate with disease-free survival Karras et al. report that high p62 expression in melanoma correlates with a high risk of metastasis. Independent of its role in autophagy, p62 recruits a subset of RNA-binding proteins in partnership with IGF2BP1 to extend the half-life of mRNAs of several pro-metastatic factors selectively in melanoma cells.