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 amplicon1. 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.
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GapmeRs were designed by J. Lai. This work was supported by the Fonds Wetenschappelijk Onderzoek (FWO; #G.0646.14N and #3G056613), Foundation Against Cancer (STK#2014-126), UGent-IOF (F2013/IOF-Advanced/676) and STK grant F/2014/376. The PDX studies were funded by GOA/14/012 (KULeuven) and KPC_29_005 (Belgian Ministries of Health). The authors wish to thank N. Samyn for help with MS, M. Van Gele for providing NHME cultures and P. Wolter for scientific discussions and his central role in the establishment of the melanoma PDX platform. E.L. is a recipient of a postdoctoral fellowship from the Marie-Curie/VIB OMICS program. M.S. is the recipient of EMBO fellowship (ALTF 648-2013). F.A. is a senior researcher from the Research Fund Flanders (FWO). P.M. and R.V. are recipients of FWO postdoctoral and PhD fellowships, respectively. D.L. is supported by the Fonds National de la Recherche (FRS/FNRS). I.D. is supported by the Institut National du Cancer PAIR melanoma (MELA13-002), the “France Génomique” consortium (ANR10-INBS-09-08), and ANR-10-LABX-0030-INRT. The I.D. laboratory is an “équipe labellisée Ligue Nationale contre le Cancer”.
Extended data figures
This file contains Supplementary Tables 1 and 2.