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

Tanmoy Mondal; Prasanna Kumar Juvvuna; Agnete Kirkeby; Sanhita Mitra; Subazini Thankaswamy Kosalai; Larissa Traxler; Falk Hertwig; Sara Wernig-Zorc; Caroline Miranda; Lily Deland; Ruth Volland; Christoph Bartenhagen; Deniz Bartsch; Sashidhar Bandaru; Anne Engesser; Santhilal Subhash; Tommy Martinsson; Helena Carén; Levent M Akyürek; Leo Kurian; Meena Kanduri; Maite Huarte; Per Kogner; Matthias Fischer; Chandrasekhar Kanduri

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

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

Authors

Tanmoy Mondal¹, Prasanna Kumar Juvvuna¹, Agnete Kirkeby², Sanhita Mitra¹, Subazini Thankaswamy Kosalai¹, Larissa Traxler³, Falk Hertwig⁴, Sara Wernig-Zorc¹, Caroline Miranda¹, Lily Deland¹, Ruth Volland⁵, Christoph Bartenhagen⁵, Deniz Bartsch⁶, Sashidhar Bandaru¹, Anne Engesser⁵, Santhilal Subhash¹, Tommy Martinsson⁷, Helena Carén⁸, Levent M Akyürek⁹, Leo Kurian⁶, Meena Kanduri¹⁰, Maite Huarte¹¹, Per Kogner¹², Matthias Fischer⁵, Chandrasekhar Kanduri¹³

Affiliations

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: [email protected].

PMID: 29533783
DOI: 10.1016/j.ccell.2018.01.020

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biomarkers, Tumor / genetics
Cell Line, Tumor
DNA-Binding Proteins / metabolism
Gene Expression Profiling / methods
Gene Expression Regulation, Neoplastic / genetics*
Humans
Mice
Neuroblastoma / genetics
Neuroblastoma / pathology
RNA, Long Noncoding / genetics*
SOX9 Transcription Factor / genetics*
Ubiquitin Thiolesterase / genetics

Substances

Biomarkers, Tumor
DNA-Binding Proteins
RNA, Long Noncoding
SOX9 Transcription Factor
SOX9 protein, human
Ubiquitin Thiolesterase