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 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.
This study aimed to investigate the effect and underlying mechanism of lncRNA CASC2 in malignant melanoma (MM).,Expression of CASC2 in MM tissues and cells was detected.,A375 cells were transfected with pc-CASC2, si-CASC2, miR-18a-5p inhibitor, or corresponding controls, and then cell proliferation, migration, and invasion were detected using MTT assay, colony formation assay, and Transwell analysis, respectively.,The relationship of miR-18a-5p and CASC2 or RUNX1 was detected by luciferase reporter assay.,The levels of CASC2 and RUNX1 were significantly reduced in MM tissues compared with normal skin tissues or cells, while the miR-18a-5p level was obviously increased (all p < 0.01).,Cell viability, colony number, migration, and invasion were significantly decreased in cells with pc-CASC2 compared with cells transfected with pcDNA3.1 (all p < 0.05).,These effects were consistent with the cells transfected with miR-18a-5p inhibitor.,The luciferase reporter assay revealed that CASC2 acted as a molecular sponge for miR-18a-5p, and RUNX1 was a target gene of miR-18a-5p.,Moreover, CASC2 overexpression promoted the expression of RUNX1, while upregulated miR-18a-5p significantly reversed the effect of CASC2 on the RUNX1 level (all p < 0.05).,Upregulated CASC2 may inhibit cell proliferation, migration, and invasion through regulating miR-18a-5p and its target gene RUNX1 in MM.