The role of the splicing regulatory kinase UHMK1 in Melanoma and its relationship with the long non-coding RNA RMEL3

Abstract

Melanoma is the type of cancer that originates from the malignant transformation of the skin's pigment cells, melanocytes, and is characterized by a high capacity to metastasize during the early stages of tumor development. Most melanomas present activating mutations in genes involved in cell growth signaling, such as the MAPK and PI3K pathways. Furthermore, somatic mutations in spliceosome and splicing factor genes are frequently observed and indicate the involvement of aberrant splicing in this type of cancer. Uhmk1 is a serine/threonine kinase that has the unique feature of having a UHM domain juxtaposed to its kinase domain. UHM motifs are protein recognition domains commonly found in splicing factors. In recent work we showed that UHMK1 regulates the phosphorylation of a variety of splicing factors and influences the global splicing pattern of cells, leading to alteration in alternative splicing events (ASEs) of hundreds of target genes. Preliminary in silico data, also showed that UHMK1 is highly expressed in melanoma samples compared to normal tissue and that 15% of patients have gene alterations that result in its elevated expression. Also, the expression of UHMK1 positively correlates with that of the lncRNA RMEL3. RMEL3 has restricted expression in melanoma, where it has an oncogenic role and function related to the MAPK and PI3K signaling pathways, especially the presence of the BRAFV600E mutation. It was shown that RMEL3 silencing in melanoma cells resulted in a decrease in UHMK1 expression, suggesting a direct relationship between these two gene products, possibly through the action of specific miRNAs.Our hypothesis is that UHMK1 participates in melanogenesis through deregulated phosphorylation of splicing factors and, consequently, dysfunction of splicing of target genes comprising RMEL3-mediated oncogenic pathways. To test our hypothesis, we aimed to i) modulate UHMK1 expression in melanoma cells and evaluate in vitro the effects of knockout and overexpression on the malignant phenotype of these cells; ii) evaluate the regulatory network and relationship between UHMK1 and RMEL3 and iii) to evaluate whether UHMK1 could be consider a potential therapeutic target in combination with inhibitors of oncogenic pathway in melanoma. (AU)