Journal Article

Melanoma addiction to the long non-coding RNA SAMMSON

Aerts, Stein, Baatsen, Pieter, Vandesompele, Jo, Vendramin, Roberto, Eyckerman, Sven, Leonelli, Carina, Rogiers, Aljosja, Hermans, Els, Lafontaine, Denis L. J., Mestdagh, Pieter, Radaelli, Enrico, Vanderheyden, Katrien, Amant, Frederic, Leucci, Eleonora, Fiers, Mark, Wouters, Jasper, Van Aelst, Stefan, Spinazzi, Marco, Marine, Jean-Christophe, van den Oord, Joost, Gevaert, Kris, Davidson, Irwin, Laurette, Patrick, de Strooper, Bart

2016

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 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