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

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.

A partial epithelial‐mesenchymal transition signature for highly aggressive colorectal cancer cells that survive under nutrient restriction

“…All three genes have been listed as mesenchymal genes in the EMTome database. In addition, SOX10 is known to be an essential marker for heterogeneity and stemness in melanoma, affecting cell-type specification and lineage differentiation [52,53]; however, its role in CRC is not yet known. Serpine1, also known as plasminogen activator inhibitor 1 (PAI-1), is a 45 kDa glycoprotein with a cleavage site for uPA.…”

ROSALINDprotects the mitochondrial translational machinery from oxidative damage

“…The sequencing yielded 920 significantly depleted transcripts upon tigecycline treatment and 1030 significantly enriched transcripts (Figure 1C), 10.6% to 13.6% of them being ncRNAs. Among the lincRNAs regulated upon the block of mitochondrial translation, we identified 2 transcripts significantly enriched in the mitochondrial matrix and 7 depleted (Figure 1D), including SAMMSON (p=0.02 log2FC=-1.46) 18,19 and LENOX (p=0.009 log2FC -1.40) 8 , previously reported to localise at mitochondria. Out of them, LINC01918 (AC104655.3), from now on ROSALIND, attracted our attention as it was the second most depleted lincRNA upon tigecycline (adj p=7.17e-19 log2FC=-3.21) (Table 1 and Figure 1D).…”

“…Slides were subsequently imaged on a Nikon C2 confocal microscope. Image J was used to quantify the properties of mitochondrial shape and network upon knock-down of ROSALIND as has been demonstrated before 8,33,34 . Briefly, 12 z-stack sections/condition of a biological triplicate containing multiple cells each, were each merged into a single image by generating a maximum intensity composite which was pre-processed using the "subtract background" (radium 1um), "sigma filter plus" (radius 0.1 μm, 2.0 sigma), "enhance local contrast/CLAHE" (block size 64, slope 2.0), "gamma correction" (0.8), and tubeness (sigma 0.361) commands on Image J.…”

Epigenetic Mechanisms Underlying Melanoma Resistance to Immune and Targeted Therapies

“…Epigenetic alterations enable more rapid and reversible modulation of cellular responses than changes to the coding genome. Melanoma tumorigenesis and progression has been linked to dysregulation of epigenetic mechanisms, such as chromatin remodeling complexes (INO80 [ 59 , 60 ], ISWI [ 61 , 62 ], and SWI/SNF [ 63 , 64 , 65 ]); histone post-translational modifications (PTMs) by histone acetyltransferases (HATs) [ 66 ], deacetylases (HDACs) [ 67 ], methyltransferases (HMTs) [ 68 ], and demethylases (HDMs) [ 69 ]; histone variants [ 70 , 71 , 72 ]; DNA [ 73 , 74 , 75 ] and RNA [ 76 , 77 , 78 ] methylation; plus non-coding [ 79 , 80 , 81 , 82 ], micro- [ 83 , 84 , 85 ], and circular [ 86 , 87 , 88 ] RNA. Unsurprisingly, epigenetic changes are also linked to immune [ 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 ] and targeted [ 98 , 99 , 100 , 101 , 102 , 103 ] therapy resistance.…”

“…SAMMSON fosters melanoma proliferation and survival by bursting mitochondrial activity and biogenesis through the p32 pathway [ 81 ]. Similarly, melanoma cells can overexpress the lncRNA LENOX (LINC00518) following LENOX genomic amplification or increased activity of SOX10 and TFAP2A [ 82 ]. LENOX works in concert with SAMMSON to promote mitochondrial oxidative phosphorylation adaptation during tumor progression and upon MAPKi treatment and resistance.…”