Abstract

Most lncRNAs display species-specific expression patterns suggesting that animal models of cancer may only incompletely recapitulate the regulatory crosstalk between lncRNAs and oncogenic pathways in humans. Among these pathways, Sonic Hedgehog (SHH) signaling is aberrantly activated in several human cancer entities. We unravel that aberrant expression of the primate-specific lncRNA HedgeHog Interacting Protein-AntiSense 1 (HHIP-AS1) is a hallmark of SHH-driven tumors including medulloblastoma and atypical teratoid/rhabdoid tumors. HHIP-AS1 is actively transcribed from a bidirectional promoter shared with SHH regulator HHIP. Knockdown of HHIP-AS1 induces mitotic spindle deregulation impairing tumorigenicity in vitro and in vivo. Mechanistically, HHIP-AS1 binds directly to the mRNA of cytoplasmic dynein 1 intermediate chain 2 (DYNC1I2) and attenuates its degradation by hsa-miR-425-5p. We uncover that neither HHIP-AS1 nor the corresponding regulatory element in DYNC1I2 are evolutionary conserved in mice. Taken together, we discover an lncRNA-mediated mechanism that enables the pro-mitotic effects of SHH pathway activation in human tumors.

Long non-coding RNAs (lncRNAs) can contribute to cancers that are driven by Sonic hedgehog (SHH) signaling. Here the authors report that lncRNA HHIP-AS1 stabilises the mRNA of dynein complex 1, thereby, promoting the pro-mitotic effects of SHH-driven tumors.

Details

Title
The HHIP-AS1 lncRNA promotes tumorigenicity through stabilization of dynein complex 1 in human SHH-driven tumors
Author
Bartl, Jasmin 1   VIAFID ORCID Logo  ; Zanini, Marco 2 ; Bernardi, Flavia 3 ; Forget, Antoine 3 ; Blümel, Lena 4 ; Talbot, Julie 5 ; Picard, Daniel 4 ; Qin, Nan 4 ; Cancila, Gabriele 5 ; Gao, Qingsong 6 ; Nath, Soumav 7 ; Koumba, Idriss Mahoungou 8 ; Wolter, Marietta 9 ; Kuonen, François 10 ; Langini, Maike 11   VIAFID ORCID Logo  ; Beez, Thomas 12 ; Munoz, Christopher 12 ; Pauck, David 4 ; Marquardt, Viktoria 4 ; Yu, Hua 5 ; Souphron, Judith 3 ; Korsch, Mascha 4   VIAFID ORCID Logo  ; Mölders, Christina 4 ; Berger, Daniel 4 ; Göbbels, Sarah 4 ; Meyer, Frauke-Dorothee 4 ; Scheffler, Björn 13   VIAFID ORCID Logo  ; Rotblat, Barak 14 ; Diederichs, Sven 15   VIAFID ORCID Logo  ; Ramaswamy, Vijay 16   VIAFID ORCID Logo  ; Suzuki, Hiromishi 17   VIAFID ORCID Logo  ; Oro, Anthony 18   VIAFID ORCID Logo  ; Stühler, Kai 19 ; Stefanski, Anja 19 ; Fischer, Ute 8   VIAFID ORCID Logo  ; Leprivier, Gabriel 9 ; Willbold, Dieter 7 ; Steger, Gerhard 20 ; Buell, Alexander 21   VIAFID ORCID Logo  ; Kool, Marcel 22 ; Lichter, Peter 23 ; Pfister, Stefan M. 24   VIAFID ORCID Logo  ; Northcott, Paul A. 6   VIAFID ORCID Logo  ; Taylor, Michael D. 25   VIAFID ORCID Logo  ; Borkhardt, Arndt 8   VIAFID ORCID Logo  ; Reifenberger, Guido 9 ; Ayrault, Olivier 5   VIAFID ORCID Logo  ; Remke, Marc 4   VIAFID ORCID Logo 

1  Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Düsseldorf, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584); Heinrich Heine University, Düsseldorf, Germany, and DKTK, partner site Essen/Düsseldorf, Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Düsseldorf, Germany (GRID:grid.411327.2) (ISNI:0000 0001 2176 9917); Heinrich Heine University, Düsseldorf, Germany, DKTK, partner site Essen/Düsseldorf, Institute of Neuropathology, Medical Faculty, Düsseldorf, Germany (GRID:grid.411327.2) (ISNI:0000 0001 2176 9917); Institute of Zoology University of Hamburg, Group for Interdisciplinary Neurobiology and Immunology-INI-research, Hamburg, Germany (GRID:grid.9026.d) (ISNI:0000 0001 2287 2617) 
2  Institut Curie, PSL Research University, CNRS UMR, INSERM, Orsay, France (GRID:grid.9026.d); Université Paris Sud, Université Paris-Saclay, CNRS UMR, INSERM U, Orsay, France (GRID:grid.5842.b) (ISNI:0000 0001 2171 2558) 
3  Institut Curie, PSL Research University, CNRS UMR, INSERM, Orsay, France (GRID:grid.5842.b); Université Paris Sud, Université Paris-Saclay, CNRS UMR, INSERM U, Orsay, France (GRID:grid.5842.b) (ISNI:0000 0001 2171 2558) 
4  Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Düsseldorf, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584); Heinrich Heine University, Düsseldorf, Germany, and DKTK, partner site Essen/Düsseldorf, Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Düsseldorf, Germany (GRID:grid.411327.2) (ISNI:0000 0001 2176 9917); Heinrich Heine University, Düsseldorf, Germany, DKTK, partner site Essen/Düsseldorf, Institute of Neuropathology, Medical Faculty, Düsseldorf, Germany (GRID:grid.411327.2) (ISNI:0000 0001 2176 9917) 
5  Institut Curie, PSL Research University, CNRS UMR, INSERM, Orsay, France (GRID:grid.411327.2); Université Paris Sud, Université Paris-Saclay, CNRS UMR, INSERM U, Orsay, France (GRID:grid.5842.b) (ISNI:0000 0001 2171 2558) 
6  St Jude Children’s Research Hospital, Memphis, USA (GRID:grid.240871.8) (ISNI:0000 0001 0224 711X) 
7  Heinrich Heine University, Institut für Physikalische Biologie and Biological-Medical Research Center (BMFZ), Düsseldorf, Germany (GRID:grid.411327.2) (ISNI:0000 0001 2176 9917); IBI- (Strukturbiochemie) and JuStruct, Forschungszentrum Jülich, Jülich, Germany (GRID:grid.8385.6) (ISNI:0000 0001 2297 375X) 
8  Heinrich Heine University, Düsseldorf, Germany, and DKTK, partner site Essen/Düsseldorf, Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Düsseldorf, Germany (GRID:grid.411327.2) (ISNI:0000 0001 2176 9917) 
9  Heinrich Heine University, Düsseldorf, Germany, DKTK, partner site Essen/Düsseldorf, Institute of Neuropathology, Medical Faculty, Düsseldorf, Germany (GRID:grid.411327.2) (ISNI:0000 0001 2176 9917) 
10  Stanford University School of Medicine, Program in Epithelial Biology, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956); Lausanne University Hospital Center, CH- Lausanne, Department of Dermatology and Venereology, Hôpital de Beaumont, Lausanne, Switzerland (GRID:grid.8515.9) (ISNI:0000 0001 0423 4662) 
11  Heinrich Heine University, Institute for Molecular Medicine, Proteome Research, Medical Faculty, Düsseldorf, Germany (GRID:grid.411327.2) (ISNI:0000 0001 2176 9917) 
12  Heinrich Heine University, Department of Neurosurgery, Medical Faculty, Düsseldorf, Germany (GRID:grid.411327.2) (ISNI:0000 0001 2176 9917) 
13  partner site University Hospital Essen, DKFZ Division of Translational Neurooncology at the West German Cancer Center (WTZ), DKTK, Düsseldorf, Germany (GRID:grid.410718.b) (ISNI:0000 0001 0262 7331) 
14  Ben-Gurion University of the Negev, Department of Life Sciences, Beer Sheva, Israel (GRID:grid.7489.2) (ISNI:0000 0004 1937 0511); The National Institute for Biotechnology in the Negev, Beer Sheva, Israel (GRID:grid.7489.2) (ISNI:0000 0004 1937 0511) 
15  University of Freiburg, DKTK, partner site Freiburg, Division of Cancer Research, Department of Thoracic Surgery, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg i.Br, Germany (GRID:grid.7489.2); Division of RNA Biology & Cancer, DKFZ, Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584) 
16  The Hospital for Sick Children, Developmental and Stem Cell Biology Program, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646); The Hospital for Sick Children, Division of Haematology/Oncology, Department of Pediatrics, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646) 
17  The Hospital for Sick Children, Developmental and Stem Cell Biology Program, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646) 
18  Stanford University School of Medicine, Program in Epithelial Biology, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956); Stanford University, Department of Dermatology, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
19  Heinrich Heine University, Molecular Proteomics Laboratory (MPL), BMFZ, Düsseldorf, Germany (GRID:grid.411327.2) (ISNI:0000 0001 2176 9917) 
20  Heinrich Heine University, Institut für Physikalische Biologie and Biological-Medical Research Center (BMFZ), Düsseldorf, Germany (GRID:grid.411327.2) (ISNI:0000 0001 2176 9917) 
21  Technical University of Denmark, Department of Biotechnology and Biomedicine, Kongens Lyngby, Denmark (GRID:grid.5170.3) (ISNI:0000 0001 2181 8870) 
22  Hopp Children´s Cancer Center (KiTZ), Heidelberg, Germany (GRID:grid.510964.f); Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584); Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands (GRID:grid.487647.e) 
23  Division of Molecular Genetics, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), and National Center for Tumor Diseases (NCT), Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584) 
24  Hopp Children´s Cancer Center (KiTZ), Heidelberg, Germany (GRID:grid.510964.f); Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584); Heidelberg University Hospital, Department of Pediatric Hematology and Oncology, Heidelberg, Germany (GRID:grid.5253.1) (ISNI:0000 0001 0328 4908) 
25  The Hospital for Sick Children, Developmental and Stem Cell Biology Program, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646); The Hospital for Sick Children, The Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646); University of Toronto, Department of Laboratory Medicine and Pathobiology, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938); The Hospital for Sick Children, Division of Neurosurgery, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-022-31574-z
ProQuest document ID
2688775770
Copyright
© The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.