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Conserved functions of rapidly evolving long noncoding RNAs : the long noncoding RNA menhir/CASC15 acts as a tumor suppressor in cutaneous melanoma

Abstract : The identification of diverse target genes involved in cancer progression is crucial to decipher the mechanisms underlying cancer and to develop effective targeted treatment therapies. LncRNAs (long noncoding RNAs) are molecularly similar to messenger RNAs but lack protein coding potential. Their deregulation and misexpression as well as the presence of mutations in lncRNA loci have been linked to diseases including cancers. Like protein-coding genes, vertebrate lncRNAs can be conserved at multiple levels (sequence, expression pattern, genomic position or synteny). In contrast to only 5% sequence conservation, more than 35% of zebrafish lncRNAs are conserved at the syntenic level to human, indicating an evolutionary pressure to preserve lncRNA position in the genome. To assess if positional conservation is a predictor of functional conservation, I implemented a reverse genetic screen assaying the role of lncRNAs in melanoma development using zebrafish, an optimal oncology model with multiple skin genetics, histological and physiological similarities with human.Using CRISPR-Cas9 genome editing technology to generate syntenic lncRNA zebrafish loss of function mutants, I profiled the impact of lncRNA loss on melanoma induced by the human NRASG12 oncogene and in human melanoma cell xenografts. Among six candidate lncRNAs, we identified menhir (MElaNoma HIndrance RNA) as a melanoma tumor suppressor. menhir zebrafish mutants display impaired melanoma aggressiveness characterized by (1) accelerated tumorigenesis, (2) decreased mutant survival, (3) increased melanoma severity and (4) increased metastatic potential due to a higher permissiveness to melanoma cell invasion. To assess if the tumor suppressor function of zebrafish menhir is conserved throughout evolution, the human putative ortholog of menhir called CASC15 (Cancer Susceptibility 15) was expressed in melanocytes of the zebrafish melanoma menhir mutant. Despite lack of sequence conservation, CASC15 expression mitigated the mutant menhir melanoma phenotype as evidenced by reduced melanoma progression, decreased tumorigenesis and enhanced survival of zebrafish affected with melanoma.Thus, our results identify a novel melanoma tumor suppressor lncRNA and show that conserved genomic location of lncRNAs can be used to posit functional conservation in vertebrates.
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Perrine Lavalou. Conserved functions of rapidly evolving long noncoding RNAs : the long noncoding RNA menhir/CASC15 acts as a tumor suppressor in cutaneous melanoma. Biochemistry, Molecular Biology. Université Paris sciences et lettres, 2018. English. ⟨NNT : 2018PSLET021⟩. ⟨tel-02538726⟩

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