The Function and Clinical Implications of Long Non-Coding RNAs in Melanoma

Metastatic melanoma is the most deadly type of skin cancer. Despite the success of immunotherapy and targeted agents, the majority of patients experience disease recurrence upon treatment and die due to their disease. Long non-coding RNAs (lncRNAs) are a new subclass of non-protein coding RNAs involved in (epigenetic) regulation of cell growth, invasion, and other important cellular functions. Consequently, recent research activities focused on the discovery of these lncRNAs in a broad spectrum of human diseases, especially cancer. Additional efforts have been undertaken to dissect the underlying molecular mechanisms employed by lncRNAs. Researchers at the Medical University of Graz summarize the growing evidence of deregulated lncRNA expression in melanoma, which is linked to tumor growth and progression. They highlight specific molecular pathways and modes of action for some well-studied lncRNAs and discuss their potential clinical implications.

Overview of all melanoma related lncRNAs

(A) Llme23 binds the protein associated splicing factor which in turn can not bind to the promoter of the proto-oncogene RAB23. BANCR increases the activity of ERK, CRAF and JNK. ANRIL inhibits the transcription of p14/p15/p16 expression by methylation of the histone H3 of the INK4b/ARF/INK4a tumor suppressor locus. UCA1 targets and inactivates miR-507 and this leads to increased levels of the pro-oncogenic transcription factor FoxM1. RMel3 decreases the level of PTEN, p27 and p38 and increases the activity of BRAF and Akt; (B) GAS5 inhibits the matrixmetalloprotease 2 which in turn decreases the ability of migration of melanoma cells. HOTAIR leads together with PRC2 to increased chromatin remodeling. MALAT1 binds to miR-22 in cutaneous melanoma promoting MMP14 and SNAIL expression. In uveal melanoma it binds to miR-140 decreasing SLUG and ADAM10 expression. PAUPAR represses HES1 expression by inhibiting histone H3K4 demethylation; (C) SPRY4-IT1 inhibits Lipin2 which converts phosphatidate to diacylglycerol. SAMMSON is co-amplified with MITF and forms a complex with p32 which stabilized mitochondrial biogenesis. Red and black T shaped bars signify reduced or downregulated proteins/miRNAs or genes. Black arrows indicate overexpressed or upregulated proteins or genes. ERK: extracellular signal-regulated kinase; CRAF: C-Raf proto-oncogene, serine/threonine kinase; JNK: JUN N-terminal kinase; ANRIL: antisense lncRNA in INK4 locus; UCA1: Urothelial carcinoma-associated 1; PTEN: phosphatase and tensin homolog; BRAF: B-Raf proto-oncogene, serine/threonine kinase; GAS5: growth arrest-specific transcript 5; HOTAIR: HOX transcript antisense RNA; PRC2: polycomb repressive complexe 2; MMP14: matrix metalloproteinase 14; SNAIL: snail family transcriptional repressor; SLUG: snail family transcriptional repressor 2; ADAM10: ADAM metallopeptidase domain 10; PAUPAR: PAX6 upstream antisense RNA; SPRY4-IT1: SPRY4 intronic transcript 1; SAMMSON: Survival associated mitochondrial melanoma-specific oncogenic non-coding RNA; MITF: melanogenesis associated transcription factor.