Melanoma addiction to the long non-coding RNA SAMMSON

• Published in: Nature (London) Vol. 531; no. 7595; pp. 518 - 522
• Main Authors: Leucci, Eleonora, Vendramin, Roberto, Spinazzi, Marco, Laurette, Patrick, Fiers, Mark, Wouters, Jasper, Radaelli, Enrico, Eyckerman, Sven, Leonelli, Carina, Vanderheyden, Katrien, Rogiers, Aljosja, Hermans, Els, Baatsen, Pieter, Aerts, Stein, Amant, Frederic, Van Aelst, Stefan, van den Oord, Joost, de Strooper, Bart, Davidson, Irwin, Lafontaine, Denis L. J., Gevaert, Kris, Vandesompele, Jo, Mestdagh, Pieter, Marine, Jean-Christophe
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.03.2016; Nature Publishing Group
• Subjects: 631/337/384/2568; 631/67/1059/602; 631/67/1813/1634; Animals; Binding sites; Cancer; Carcinogenesis - genetics; Carcinogenesis - pathology; Cell Lineage; Cell Proliferation; Cell Survival; Chromosomes, Human, Pair 3 - genetics; Clone Cells - metabolism; Clone Cells - pathology; Female; Gene amplification; Gene Amplification - genetics; Gene Knockdown Techniques; Genetic aspects; Genomes; Health aspects; Human health and pathology; Humanities and Social Sciences; Humans; Kinases; letter; Life Sciences; Melanoma; Melanoma - genetics; Melanoma - pathology; Melanoma - therapy; Metabolism; Mice; Microphthalmia-Associated Transcription Factor - genetics; Mitochondria - genetics; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial Proteins - metabolism; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; Molecular Targeted Therapy; multidisciplinary; Oncogenes - genetics; Oncology, Experimental; Proteins; Ribonucleic acid; RNA; RNA, Long Noncoding - genetics; RNA, Long Noncoding - therapeutic use; Science; SOXE Transcription Factors - metabolism; Xenograft Model Antitumor Assays; Belgium; Long Noncoding; Pair 3; Cell Proliferation; RNA; Humans; Molecular Targeted Therapy; Mitochondrial Proteins; Carcinogenesis; Gene Knockdown Techniques; SOXE Transcription Factors; Female; Clone Cells; Chromosomes; Oncogenes; Mitogen-Activated Protein Kinases; Human; Cell Survival; mitochondria; melanoma; Xenograft Model Antitumor Assays; Microphthalmia-Associated Transcription Factor; Cell Lineage; Gene Amplification; Animals; Mice
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature17161

A known oncogene, MITF , resides in a region of chromosome 3 that is amplified in melanomas and associated with poor prognosis; now, a long non-coding RNA gene, SAMMSON , is shown to also lie in this region, to also act as a melanoma-specific survival oncogene, and to be a promising therapeutic target for anti-melanoma therapy. An oncogenic non-coding RNA The known oncogene MITF is found in the 3p13–3p14 region of chromosome 3 that is amplified in melanomas and associated with poor prognosis. This study shows that a long non-coding RNA, SAMMSON , also lies in this region and is co-gained with MITF . SAMMSON interacts with p32 and thereby affects mitochondrial function in a pro-oncogenic manner. SAMMSON depletion sensitizes melanoma cells to MAPK-targeting therapeutics in vivo and in patient-derived xenograft models. These results point to SAMMSON as a potentially useful biomarker for malignancy and as an anti-melanoma therapeutic target. Focal amplifications of chromosome 3p13–3p14 occur in about 10% of melanomas and are associated with a poor prognosis. The melanoma-specific oncogene MITF resides at the epicentre of this amplicon 1 . However, whether other loci present in this amplicon also contribute to melanomagenesis is unknown. Here we show that the recently annotated long non-coding RNA (lncRNA) gene SAMMSON is consistently co-gained with MITF . In addition, SAMMSON is a target of the lineage-specific transcription factor SOX10 and its expression is detectable in more than 90% of human melanomas. Whereas exogenous SAMMSON increases the clonogenic potential in trans , SAMMSON knockdown drastically decreases the viability of melanoma cells irrespective of their transcriptional cell state and BRAF , NRAS or TP53 mutational status. Moreover, SAMMSON targeting sensitizes melanoma to MAPK-targeting therapeutics both in vitro and in patient-derived xenograft models. Mechanistically, SAMMSON interacts with p32, a master regulator of mitochondrial homeostasis and metabolism, to increase its mitochondrial targeting and pro-oncogenic function. Our results indicate that silencing of the lineage addiction oncogene SAMMSON disrupts vital mitochondrial functions in a cancer-cell-specific manner; this silencing is therefore expected to deliver highly effective and tissue-restricted anti-melanoma therapeutic responses.