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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Disease Progression
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Melanoma / genetics
  • Melanoma / metabolism*
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics*
  • Mice
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / genetics*
  • Neoplasm Transplantation
  • Protein Interaction Maps
  • Proteomics / methods
  • RNA Stability
  • RNA, Messenger / chemistry*
  • RNA-Binding Proteins / metabolism*
  • Sequestosome-1 Protein / metabolism*
  • Tissue Array Analysis

Substances

  • FERMT2 protein, human
  • IMP-1 protein, human
  • Membrane Proteins
  • Neoplasm Proteins
  • RNA, Messenger
  • RNA-Binding Proteins
  • SQSTM1 protein, human
  • Sequestosome-1 Protein