Publication Date:
2016-03-25
Description:
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. 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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- England -- Nature. 2016 Mar 24;531(7595):518-22. doi: 10.1038/nature17161.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory For Molecular Cancer Biology, Center for Human Genetics, KULeuven, Herestraat 49, 3000 Leuven, Belgium. ; Center for the Biology of Disease, VIB, Herestraat 49, 3000 Leuven, Belgium. ; Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), Rue Laurent Fries 1, 67404 Illkirch, France. ; Laboratory of Translational Cell and Tissue Research, Department of Pathology, KULeuven and UZ Leuven, Herestraat 49, 3000 Leuven, Belgium. ; Mouse Histopathology Core Facility, Center for the Biology of Disease, VIB-KULeuven, Herestraat 49, 3000 Leuven, Belgium. ; Medical Biotechnology Center, VIB, Albert Baertsoenkaai 3, 9000 Gent, Belgium. ; Department of Biochemistry, Gent University, Albert Baertsoenkaai 3, 9000 Gent, Belgium. ; Center for Medical Genetics, Gent University, De Pintelaan 185, 9000 Gent, Belgium. ; Cancer Research Institute Gent, Gent University, De Pintelaan 185, 9000 Gent, Belgium. ; Gynaecologische Oncologie, KU Leuven, Herestraat 49, 3000 Leuven, Belgium. ; Laboratory of Computational Biology, Center for Human Genetics, KULeuven, Herestraat 49, 3000 Leuven, Belgium. ; Department of Applied Mathematics, Computer Science and Statistics, Gent University, De Pintelaan 185, 9000 Gent, Belgium. ; Department of Mathematics, KU Leuven, Celestijnenlann 200B, 3001 Leuven, Belgium. ; RNA Molecular Biology, Center for Microscopy and Molecular Imaging, Universite Libre de Bruxelles (ULB), rue des Professeurs Jeener et Brachet 12, 6041 Charleroi, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27008969" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Carcinogenesis/genetics/pathology
;
Cell Lineage
;
Cell Proliferation
;
Cell Survival
;
Chromosomes, Human, Pair 3/genetics
;
Clone Cells/metabolism/pathology
;
Female
;
Gene Amplification/genetics
;
Gene Knockdown Techniques
;
Humans
;
Melanoma/*genetics/*pathology/therapy
;
Mice
;
Microphthalmia-Associated Transcription Factor/genetics
;
Mitochondria/genetics/metabolism/pathology
;
Mitochondrial Proteins/metabolism
;
Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolism
;
Molecular Targeted Therapy
;
Oncogenes/*genetics
;
RNA, Long Noncoding/*genetics/therapeutic use
;
SOXE Transcription Factors/metabolism
;
Xenograft Model Antitumor Assays
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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