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

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 meta...

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Veröffentlicht in:EMBO reports Jg. 22; H. 3; S. e50852 - n/a
Hauptverfasser: Melixetian, Marine, Bossi, Daniela, Mihailovich, Marija, Punzi, Simona, Barozzi, Iros, Marocchi, Federica, Cuomo, Alessandro, Bonaldi, Tiziana, Testa, Giuseppe, Marine, Jean-Christophe, Leucci, Eleonora, Minucci, Saverio, Pelicci, Pier Giuseppe, Lanfrancone, Luisa
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 03.03.2021
Springer Nature B.V
John Wiley and Sons Inc
Schlagworte:
ATF4
Binding
Depletion
Drug resistance
EMBO03
EMBO36
EMBO37
Genotype & phenotype
integrated stress response
lncRNAs
MEK inhibitors
Melanoma
Metastases
Metastasis
Non-coding RNA
Nutrients
Phenotypes
Phosphorylation
Protein biosynthesis
Protein synthesis
Proteins
Reversion
Ribonucleic acid
Ribosomes
RNA
Translation
translational reprogramming
Tumors
lncRNAs
melanoma
translational reprogramming
ATF4
integrated stress response
ISSN:1469-221X, 1469-3178, 1469-3178
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Zusammenfassung: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. SYNOPSIS Long non-coding RNA TINCR blocks the acquisition of invasive phenotypes in melanoma, including drug resistance and metastasis dissemination. TINCR targets RNAs associated with invasive phenotypes, preventing their interaction with ribosomes. High TINCR levels prevent translational reprogramming and ATF4 translation, maintaining proliferative, epithelial-like states. TINCR downregulation leads to translational reprogramming and ATF4 activation, promoting invasion in nutrient-rich conditions. TINCR interacts with selected integrated stress response RNAs, preventing their binding to the translating ribosomes. Graphical Abstract Long non-coding RNA TINCR blocks the acquisition of invasive phenotypes in melanoma, including drug resistance and metastasis dissemination. TINCR targets RNAs associated with invasive phenotypes, preventing their interaction with ribosomes.
Bibliographie:ObjectType-Article-1
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ISSN:1469-221X
1469-3178
1469-3178
DOI:10.15252/embr.202050852