Abstract

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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Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

Mass spectrometry data have been deposited in the Proteomics Identifications Database under accession numbers PXD002565. Gene expression data have been deposited in the Gene Expression Omnibus under accession number GSE70180.

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Acknowledgements

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”.

Author information

Author notes

    • Pieter Mestdagh
    •  & Jean-Christophe Marine

    These authors contributed equally to this work.

Affiliations

  1. Laboratory For Molecular Cancer Biology, Center for Human Genetics, KULeuven, Herestraat 49, 3000 Leuven, Belgium

    • Eleonora Leucci
    • , Roberto Vendramin
    • , Aljosja Rogiers
    •  & Jean-Christophe Marine
  2. Center for the Biology of Disease, VIB, Herestraat 49, 3000 Leuven, Belgium

    • Eleonora Leucci
    • , Roberto Vendramin
    • , Marco Spinazzi
    • , Mark Fiers
    • , Aljosja Rogiers
    • , Pieter Baatsen
    • , Bart de Strooper
    •  & Jean-Christophe Marine
  3. Institut de Génétique et de Biologie Moleculaire et Cellulaire (IGBMC), Rue Laurent Fries 1, 67404 Illkirch, France

    • Patrick Laurette
    •  & Irwin Davidson
  4. Laboratory of Translational Cell and Tissue Research, Department of Pathology, KULeuven and UZ Leuven, Herestraat 49, 3000 Leuven, Belgium

    • Jasper Wouters
    •  & Joost van den Oord
  5. Mouse Histopathology Core Facility, Center for the Biology of Disease, VIB-KULeuven, Herestraat 49, 3000 Leuven, Belgium

    • Enrico Radaelli
  6. Medical Biotechnology Center, VIB, Albert Baertsoenkaai 3, 9000 Gent, Belgium

    • Sven Eyckerman
    •  & Kris Gevaert
  7. Department of Biochemistry, Gent University, Albert Baertsoenkaai 3, 9000 Gent, Belgium

    • Sven Eyckerman
    •  & Kris Gevaert
  8. Center for Medical Genetics, Gent University, De Pintelaan 185, 9000 Gent, Belgium

    • Carina Leonelli
    • , Katrien Vanderheyden
    • , Jo Vandesompele
    •  & Pieter Mestdagh
  9. Cancer Research Institute Gent, Gent University, De Pintelaan 185, 9000 Gent, Belgium

    • Carina Leonelli
    • , Katrien Vanderheyden
    • , Jo Vandesompele
    •  & Pieter Mestdagh
  10. Gynaecologische Oncologie, KU Leuven, Herestraat 49, 3000 Leuven, Belgium

    • Els Hermans
    •  & Frederic Amant
  11. Laboratory of Computational Biology, Center for Human Genetics, KULeuven, Herestraat 49, 3000 Leuven, Belgium

    • Stein Aerts
  12. Department of Applied Mathematics, Computer Science and Statistics, Gent University, De Pintelaan 185, 9000 Gent, Belgium

    • Stefan Van Aelst
  13. Department of Mathematics, KU Leuven, Celestijnenlann 200B, 3001 Leuven, Belgium

    • Stefan Van Aelst
  14. RNA Molecular Biology, Center for Microscopy and Molecular Imaging, Université Libre de Bruxelles (ULB), rue des Professeurs Jeener et Brachet 12, 6041 Charleroi, Belgium

    • Denis L. J. Lafontaine

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Contributions

E.L. and R.V. performed most experiments. M.S. performed the experiments described in Fig.3f. P.L., S.A. and I.D. provided ChIP-seq data. J.W. and J.v.d.O. provided melanoma clinical samples. J.v.d.O. and E.R. provided histopathology support. S.E. and K.G. performed the mass spectrometric measurement and analysis. C.L., K.V., S.V.A. and P.M. performed copy number variant analysis and profiling experiments and interpretation of the data. A.R., E.H. and F.A. provided support with the PDX models. P.B. provided technical support for the electron microscopy. P.M., M.F. and S.A. provided bioinformatics support. D.L.J.L., B.d.S., P.M. and J.V. helped with the interpretation of the data. J.-C.M. and E.L. designed most of the experiments and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jean-Christophe Marine.

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DOI

https://doi.org/10.1038/nature17161

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