Abstract
Melanomas are well-known for their altered mRNA expression profiles. Yet, the specific contribution of mRNA binding proteins (mRBPs) to melanoma development remains unclear. Here we identify a cluster of melanoma-enriched genes under the control of CUGBP Elav-like family member 1 (CELF1). CELF1 was discovered with a distinct prognostic value in melanoma after mining the genomic landscape of the 692 known mRBPs across different cancer types. Genome-wide transcriptomic, proteomic, and RNA-immunoprecipitation studies, together with loss-of-function analyses in cell lines, and histopathological evaluation in clinical biopsies, revealed an intricate repertoire of CELF1-RNA interactors with minimal overlap with other malignancies. This systems approach uncovered the oncogene DEK as an unexpected target and downstream effector of CELF1. Importantly, CELF1 and DEK were found to represent early-induced melanoma genes and adverse indicators of overall patient survival. These results underscore novel roles of CELF1 in melanoma, illustrating tumor type-restricted functions of RBPs in cancer.
Highlights
Melanomas are well-known for their altered mRNA expression profiles
To interrogate whether these alterations apply to malignant melanoma, the 692 known human mRBPs5 were mined throughout The Cancer Genome Atlas (TCGA), which includes comprehensive genomic and expression information from 479 human cutaneous melanomas[9]
We show that melanomas, despite presenting with the largest mutational rate described to date[6], and accumulating a plethora of transcriptomic changes[9], largely spare the more than 650 mRNA binding proteins (mRBPs) from mutations or copy number variations (CNVs)
Summary
Melanomas are well-known for their altered mRNA expression profiles. Yet, the specific contribution of mRNA binding proteins (mRBPs) to melanoma development remains unclear. Genome-wide transcriptomic, proteomic, and RNA-immunoprecipitation studies, together with loss-of-function analyses in cell lines, and histopathological evaluation in clinical biopsies, revealed an intricate repertoire of CELF1-RNA interactors with minimal overlap with other malignancies. Expression studies in clinical biopsies, and comprehensive transcriptomic and proteomic analyses of RBP-dependent functions become more important in the light of a broad spectrum of synonymous mutations in melanoma cells, at intergenic sites, but at untranslated (UTR) regions of mRNAs7,18. We mined clinical data sets for an unbiased characterization of the genomic status (mutations, amplifications, deletions, translocations) of all known mRBPs in human melanomas These studies failed to reveal characteristic copy number changes reported in less genetically altered cancers. Transcriptomic, histological and functional analyses, together with studies of patient prognosis revealed new roles and melanomaenriched targets of CELF1, which provide insight on selective RBPs fueling tumor development
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