Long non-coding RNA TINCR suppresses metastatic melanoma dissemination by preventing ATF4 translation

Marine Melixetian, Daniela Bossi, Marija Mihailovich, Simona Punzi, Iros Barozzi, Federica Marocchi, Alessandro Cuomo, Tiziana Bonaldi, Giuseppe Testa, Jean Christophe Marine, Eleonora Leucci, Saverio Minucci, Pier Giuseppe Pelicci, Luisa Lanfrancone

Research output: Contribution to journalArticlepeer-review

Abstract

Transition from proliferative-to-invasive phenotypes promotes metastasis and therapy resistance in melanoma. Reversion of the invasive phenotype, however, is challenged by the poor understanding of mechanisms underlying its maintenance. Here, we report that the lncRNA TINCR is down-regulated in metastatic melanoma and its silencing increases the expression levels of invasive markers, in vitro migration, in vivo tumor growth, and resistance to BRAF and MEK inhibitors. The critical mediator is ATF4, a central player of the integrated stress response (ISR), which is activated in TINCR-depleted cells in the absence of starvation and eIF2α phosphorylation. TINCR depletion increases global protein synthesis and induces translational reprogramming, leading to increased translation of mRNAs encoding ATF4 and other ISR proteins. Strikingly, re-expression of TINCR in metastatic melanoma suppresses the invasive phenotype, reduces numbers of tumor-initiating cells and metastasis formation, and increases drug sensitivity. Mechanistically, TINCR interacts with mRNAs associated with the invasive phenotype, including ATF4, preventing their binding to ribosomes. Thus, TINCR is a suppressor of the melanoma invasive phenotype, which functions in nutrient-rich conditions by repressing translation of selected ISR RNAs.

Original languageEnglish
Article numbere50852
JournalEMBO Reports
Volume22
Issue number3
DOIs
Publication statusPublished - Mar 3 2021

Keywords

  • ATF4
  • integrated stress response
  • lncRNAs
  • melanoma
  • translational reprogramming

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

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