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.

Long non-coding RNA TINCR suppresses metastatic melanoma dissemination by preventing ATF4 translation / M. Melixetian, D. Bossi, M. Mihailovich, S. Punzi, I. Barozzi, F. Marocchi, A. Cuomo, T. Bonaldi, G. Testa, J. Marine, E. Leucci, S. Minucci, P. Pelicci, L. Lanfrancone. - In: EMBO REPORTS. - ISSN 1469-221X. - 22:3(2021 Mar 03), pp. e50852.1-e50852.19. [10.15252/embr.202050852]

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

D. Bossi;S. Punzi;F. Marocchi;T. Bonaldi
Investigation
;
G. Testa;S. Minucci;P. Pelicci
Penultimo
;
2021

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.
ATF4; integrated stress response; lncRNAs; melanoma; translational reprogramming; Activating Transcription Factor 4; Cell Line, Tumor; Humans; Phosphorylation; RNA, Messenger; Melanoma; Pharmaceutical Preparations; RNA, Long Noncoding
Settore BIO/13 - Biologia Applicata
Settore BIO/11 - Biologia Molecolare
Settore MED/06 - Oncologia Medica
3-mar-2021
feb-2021
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/947596
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