Novel Biological Strategies for Melanoma Therapy: A Focus on lncRNAs and Their Targeting

Simple Summary Although available treatments for metastatic melanoma have significantly improved the clinical outcome of patients, there is still a portion of patients whose tumor progresses. Therefore, new therapeutic approaches for melanoma are needed, which could include targeting specific lncRNAs altered in this neoplasm. Indeed, the lncRNAs aberrant expression influences several hallmarks of melanoma cells and contributes to the acquisition of drug resistance. This review focuses on the main lncRNAs altered in melanoma, highlighting the consequences of their aberrant expression on the phenotypic plasticity of melanoma cells. Furthermore, we investigated their possible targeting using nucleic acid-based techniques or natural products such as phytochemicals. Finally, we explored the advances in nanotechnology for the specific delivery of lncRNAs into cancer tissues and to avoid potential side effects. Abstract Increasing evidence revealed that restoring the correct expression of lncRNAs could have implications in the management of melanoma patients. In this context, here, we aim to dissect the main characteristics of lncRNAs altered in melanoma and their crosstalk with the signaling pathways involved in the progression of this disease. We also highlight the role of nucleic acid-based techniques and natural compounds (i.e., phytochemicals) as a therapeutic tool to increase or silence their expression in cancer cells. Finally, we explore the advances in nanotechnologies as delivery systems to efficiently carry these chemicals into cancer cells, thus limiting their potential off-target effects. The analysis of the literature showed that HOTAIR, MALAT1, and H19 are the oncogenic lncRNAs most studied in melanoma, while MEG3 is an important tumor suppressor decreased in this cancer. The aberrant expression of these lncRNAs affects several hallmarks of cancer, e.g., proliferation, motility, and epithelial to mesenchymal transition, promoting the melanoma plasticity and drug resistance. In this frame, siRNA, antisense oligonucleotide, and CRISPR-Cas9 genome editing appear to be the most effective nucleic acid strategies to restore the physiologic expression of lncRNA, while curcumin, resveratrol, and quercetin are the main phytochemicals able to target and influence the expression of lncRNAs altered in cancer. Overall, this study provides a comprehensive overview regarding the role of lncRNAs in the phenotype plasticity of melanoma cells and their potential targeting using RNA-based therapy and natural products.