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The LncRNA LENOX Interacts with RAP2C to Regulate Metabolism and Promote Resistance to MAPK Inhibition in Melanoma

Tumor heterogeneity is a key feature of melanomas that hinders development of effective treatments. Aiming to overcome this, we identified LINC00518 (LENOX; lincRNA-enhancer of oxidative phosphorylation) as a melanoma-specific lncRNA expressed in all known melanoma cell states and essential for mela...

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Autores principales: Gambi, Giovanni, Mengus, Gabrielle, Davidson, Guillaume, Demesmaeker, Ewout, Cuomo, Alessandro, Bonaldi, Tiziana, Katopodi, Vicky, Malouf, Gabriel G., Leucci, Eleonora, Davidson, Irwin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9755964/
https://www.ncbi.nlm.nih.gov/pubmed/36214632
http://dx.doi.org/10.1158/0008-5472.CAN-22-0959
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author Gambi, Giovanni
Mengus, Gabrielle
Davidson, Guillaume
Demesmaeker, Ewout
Cuomo, Alessandro
Bonaldi, Tiziana
Katopodi, Vicky
Malouf, Gabriel G.
Leucci, Eleonora
Davidson, Irwin
author_facet Gambi, Giovanni
Mengus, Gabrielle
Davidson, Guillaume
Demesmaeker, Ewout
Cuomo, Alessandro
Bonaldi, Tiziana
Katopodi, Vicky
Malouf, Gabriel G.
Leucci, Eleonora
Davidson, Irwin
author_sort Gambi, Giovanni
collection PubMed
description Tumor heterogeneity is a key feature of melanomas that hinders development of effective treatments. Aiming to overcome this, we identified LINC00518 (LENOX; lincRNA-enhancer of oxidative phosphorylation) as a melanoma-specific lncRNA expressed in all known melanoma cell states and essential for melanoma survival in vitro and in vivo. Mechanistically, LENOX promoted association of the RAP2C GTPase with mitochondrial fission regulator DRP1, increasing DRP1 S637 phosphorylation, mitochondrial fusion, and oxidative phosphorylation. LENOX expression was upregulated following treatment with MAPK inhibitors, facilitating a metabolic switch from glycolysis to oxidative phosphorylation and conferring resistance to MAPK inhibition. Consequently, combined silencing of LENOX and RAP2C synergized with MAPK inhibitors to eradicate melanoma cells. Melanomas are thus addicted to the lncRNA LENOX, which acts to optimize mitochondrial function during melanoma development and progression. SIGNIFICANCE: The lncRNA LENOX is a novel regulator of melanoma metabolism, which can be targeted in conjunction with MAPK inhibitors to eradicate melanoma cells.
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spelling pubmed-97559642023-01-05 The LncRNA LENOX Interacts with RAP2C to Regulate Metabolism and Promote Resistance to MAPK Inhibition in Melanoma Gambi, Giovanni Mengus, Gabrielle Davidson, Guillaume Demesmaeker, Ewout Cuomo, Alessandro Bonaldi, Tiziana Katopodi, Vicky Malouf, Gabriel G. Leucci, Eleonora Davidson, Irwin Cancer Res Molecular Cell Biology Tumor heterogeneity is a key feature of melanomas that hinders development of effective treatments. Aiming to overcome this, we identified LINC00518 (LENOX; lincRNA-enhancer of oxidative phosphorylation) as a melanoma-specific lncRNA expressed in all known melanoma cell states and essential for melanoma survival in vitro and in vivo. Mechanistically, LENOX promoted association of the RAP2C GTPase with mitochondrial fission regulator DRP1, increasing DRP1 S637 phosphorylation, mitochondrial fusion, and oxidative phosphorylation. LENOX expression was upregulated following treatment with MAPK inhibitors, facilitating a metabolic switch from glycolysis to oxidative phosphorylation and conferring resistance to MAPK inhibition. Consequently, combined silencing of LENOX and RAP2C synergized with MAPK inhibitors to eradicate melanoma cells. Melanomas are thus addicted to the lncRNA LENOX, which acts to optimize mitochondrial function during melanoma development and progression. SIGNIFICANCE: The lncRNA LENOX is a novel regulator of melanoma metabolism, which can be targeted in conjunction with MAPK inhibitors to eradicate melanoma cells. American Association for Cancer Research 2022-12-16 2022-10-10 /pmc/articles/PMC9755964/ /pubmed/36214632 http://dx.doi.org/10.1158/0008-5472.CAN-22-0959 Text en ©2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
spellingShingle Molecular Cell Biology
Gambi, Giovanni
Mengus, Gabrielle
Davidson, Guillaume
Demesmaeker, Ewout
Cuomo, Alessandro
Bonaldi, Tiziana
Katopodi, Vicky
Malouf, Gabriel G.
Leucci, Eleonora
Davidson, Irwin
The LncRNA LENOX Interacts with RAP2C to Regulate Metabolism and Promote Resistance to MAPK Inhibition in Melanoma
title The LncRNA LENOX Interacts with RAP2C to Regulate Metabolism and Promote Resistance to MAPK Inhibition in Melanoma
title_full The LncRNA LENOX Interacts with RAP2C to Regulate Metabolism and Promote Resistance to MAPK Inhibition in Melanoma
title_fullStr The LncRNA LENOX Interacts with RAP2C to Regulate Metabolism and Promote Resistance to MAPK Inhibition in Melanoma
title_full_unstemmed The LncRNA LENOX Interacts with RAP2C to Regulate Metabolism and Promote Resistance to MAPK Inhibition in Melanoma
title_short The LncRNA LENOX Interacts with RAP2C to Regulate Metabolism and Promote Resistance to MAPK Inhibition in Melanoma
title_sort lncrna lenox interacts with rap2c to regulate metabolism and promote resistance to mapk inhibition in melanoma
topic Molecular Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9755964/
https://www.ncbi.nlm.nih.gov/pubmed/36214632
http://dx.doi.org/10.1158/0008-5472.CAN-22-0959
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