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Supplementary Fig-8 from The LncRNA LENOX Interacts with RAP2C to Regulate Metabolism and Promote Resistance to MAPK Inhibition in Melanoma

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posted on 2023-03-31, 06:03 authored by Giovanni Gambi, Gabrielle Mengus, Guillaume Davidson, Ewout Demesmaeker, Alessandro Cuomo, Tiziana Bonaldi, Vicky Katopodi, Gabriel G. Malouf, Eleonora Leucci, Irwin Davidson

LENOX regulates mitochondrial morphology

Funding

ITMO Cancer

Ligue Nationale Contre le Cancer

Melanoma Research Alliance (MRA)

Amanda and Jonathan Eilian young investigator award

Belgian federation for cancer

Agence Nationale de la Recherche (ANR)

European Proteomics Infrastructure Consortium providing access (EPIC-XS)

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ARTICLE ABSTRACT

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. 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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