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Cancer Cell. 2018 Mar 12;33(3):417-434.e7. doi: 10.1016/j.ccell.2018.01.020.

Sense-Antisense lncRNA Pair Encoded by Locus 6p22.3 Determines Neuroblastoma Susceptibility via the USP36-CHD7-SOX9 Regulatory Axis.

Author information

1
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden.
2
Wallenberg Neuroscience Center, Lund University, 22184 Lund, Sweden; Danish Stem Cell Center (DanStem), University of Copenhagen, 2200 Copenhagen, Denmark.
3
Wallenberg Neuroscience Center, Lund University, 22184 Lund, Sweden.
4
Department of Experimental Pediatric Oncology, University Children's Hospital, and Center for Molecular Medicine (CMMC), Medical Faculty, University of Cologne, 50937 Cologne, Germany; Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany.
5
Department of Experimental Pediatric Oncology, University Children's Hospital, and Center for Molecular Medicine (CMMC), Medical Faculty, University of Cologne, 50937 Cologne, Germany.
6
Center for Molecular Medicine Cologne, Institute for Neurophysiology, The Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases, University of Cologne, Cologne, Germany.
7
Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden.
8
Sahlgrenska Cancer Center, Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden.
9
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden.
10
Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden.
11
Center for Applied Medical Research (CIMA), University of Navarra, Pio XII, 55, 31008 Pamplona, Spain.
12
Childhood Cancer Research Unit, Astrid Lindgren Children's Hospital, Karolinska University Hospital, 17176 Stockholm, Sweden.
13
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden. Electronic address: kanduri.chandrasekhar@gu.se.

Abstract

Trait-associated loci often map to genomic regions encoding long noncoding RNAs (lncRNAs), but the role of these lncRNAs in disease etiology is largely unexplored. We show that a pair of sense/antisense lncRNA (6p22lncRNAs) encoded by CASC15 and NBAT1 located at the neuroblastoma (NB) risk-associated 6p22.3 locus are tumor suppressors and show reduced expression in high-risk NBs. Loss of functional synergy between 6p22lncRNAs results in an undifferentiated state that is maintained by a gene-regulatory network, including SOX9 located on 17q, a region frequently gained in NB. 6p22lncRNAs regulate SOX9 expression by controlling CHD7 stability via modulating the cellular localization of USP36, encoded by another 17q gene. This regulatory nexus between 6p22.3 and 17q regions may lead to potential NB treatment strategies.

KEYWORDS:

CASC15; CHD7; NBAT1; SOX9; USP36; lncRNA; long noncoding RNA; neuroblastoma; neuronal differentiation; ubiquitination

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