The HHIP-AS1 lncRNA promotes tumorigenicity through stabilization of dynein complex 1 in human SHH-driven tumors

Jasmin Bartl; Marco Zanini; Flavia Bernardi; Antoine Forget; Lena Blümel; Julie Talbot; Daniel Picard; Nan Qin; Gabriele Cancila; Qingsong Gao; Soumav Nath; Idriss Mahoungou Koumba; Marietta Wolter; François Kuonen; Maike Langini; Thomas Beez; Christopher Munoz; David Pauck; Viktoria Marquardt; Hua Yu; Judith Souphron; Mascha Korsch; Christina Mölders; Daniel Berger; Sarah Göbbels; Frauke-Dorothee Meyer; Björn Scheffler; Barak Rotblat; Sven Diederichs; Vijay Ramaswamy; Hiromishi Suzuki; Anthony Oro; Kai Stühler; Anja Stefanski; Ute Fischer; Gabriel Leprivier; Dieter Willbold; Gerhard Steger; Alexander Buell; Marcel Kool; Peter Lichter; Stefan M Pfister; Paul A Northcott; Michael D Taylor; Arndt Borkhardt; Guido Reifenberger; Olivier Ayrault; Marc Remke

doi:10.1038/s41467-022-31574-z

The HHIP-AS1 lncRNA promotes tumorigenicity through stabilization of dynein complex 1 in human SHH-driven tumors

Nat Commun. 2022 Jul 13;13(1):4061. doi: 10.1038/s41467-022-31574-z.

Authors

Jasmin Bartl^#^{1

2

3

4}, Marco Zanini^#^{5

6}, Flavia Bernardi^#^{5

6}, Antoine Forget^{5

6}, Lena Blümel^{7

8

9}, Julie Talbot^{5

6}, Daniel Picard^{7

8

9}, Nan Qin^{7

8

9}, Gabriele Cancila^{5

6}, Qingsong Gao¹⁰, Soumav Nath^{11

12}, Idriss Mahoungou Koumba⁸, Marietta Wolter⁹, François Kuonen^{13

14}, Maike Langini¹⁵, Thomas Beez¹⁶, Christopher Munoz¹⁶, David Pauck^{7

8

9}, Viktoria Marquardt^{7

8

9}, Hua Yu^{5

6}, Judith Souphron^{5

6}, Mascha Korsch^{7

8

9}, Christina Mölders^{7

8

9}, Daniel Berger^{7

8

9}, Sarah Göbbels^{7

8

9}, Frauke-Dorothee Meyer^{7

8

9}, Björn Scheffler¹⁷, Barak Rotblat^{18

19}, Sven Diederichs^{20

21}, Vijay Ramaswamy^{22

23}, Hiromishi Suzuki²², Anthony Oro^{13

24}, Kai Stühler²⁵, Anja Stefanski²⁵, Ute Fischer⁸, Gabriel Leprivier⁹, Dieter Willbold^{11

12}, Gerhard Steger¹¹, Alexander Buell²⁶, Marcel Kool^{27

28

29}, Peter Lichter³⁰, Stefan M Pfister^{27

28

31}, Paul A Northcott¹⁰, Michael D Taylor^{22

32

33

34}, Arndt Borkhardt⁸, Guido Reifenberger⁹, Olivier Ayrault^{35

36}, Marc Remke^{37

38

39}

Affiliations

¹ Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany. [email protected].
² Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany, and DKTK, partner site Essen/Düsseldorf, Düsseldorf, Germany. [email protected].
³ Institute of Neuropathology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany, DKTK, partner site Essen/Düsseldorf, Düsseldorf, Germany. [email protected].
⁴ Group for Interdisciplinary Neurobiology and Immunology-INI-research, Institute of Zoology University of Hamburg, Hamburg, Germany. [email protected].
⁵ Institut Curie, PSL Research University, CNRS UMR, INSERM, Orsay, France.
⁶ Université Paris Sud, Université Paris-Saclay, CNRS UMR, INSERM U, Orsay, France.
⁷ Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany.
⁸ Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany, and DKTK, partner site Essen/Düsseldorf, Düsseldorf, Germany.
⁹ Institute of Neuropathology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany, DKTK, partner site Essen/Düsseldorf, Düsseldorf, Germany.
¹⁰ St Jude Children's Research Hospital, Memphis, TN, USA.
¹¹ Institut für Physikalische Biologie and Biological-Medical Research Center (BMFZ), Heinrich Heine University, Düsseldorf, Germany.
¹² IBI- (Strukturbiochemie) and JuStruct, Forschungszentrum Jülich, Jülich, Germany.
¹³ Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA.
¹⁴ Department of Dermatology and Venereology, Hôpital de Beaumont, Lausanne University Hospital Center, CH- Lausanne, Lausanne, Switzerland.
¹⁵ Institute for Molecular Medicine, Proteome Research, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
¹⁶ Department of Neurosurgery, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
¹⁷ DKFZ Division of Translational Neurooncology at the West German Cancer Center (WTZ), DKTK, partner site University Hospital Essen, Düsseldorf, Germany.
¹⁸ Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
¹⁹ The National Institute for Biotechnology in the Negev, Beer Sheva, Israel.
²⁰ Division of Cancer Research, Department of Thoracic Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, DKTK, partner site Freiburg, Freiburg i.Br, Germany.
²¹ Division of RNA Biology & Cancer, DKFZ, Heidelberg, Germany.
²² Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
²³ Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
²⁴ Department of Dermatology, Stanford University, Stanford, CA, USA.
²⁵ Molecular Proteomics Laboratory (MPL), BMFZ, Heinrich Heine University, Düsseldorf, Germany.
²⁶ Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark.
²⁷ Hopp Children´s Cancer Center (KiTZ), Heidelberg, Germany.
²⁸ Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
²⁹ Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
³⁰ Division of Molecular Genetics, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
³¹ Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.
³² The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
³³ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
³⁴ Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario, Canada.
³⁵ Institut Curie, PSL Research University, CNRS UMR, INSERM, Orsay, France. [email protected].
³⁶ Université Paris Sud, Université Paris-Saclay, CNRS UMR, INSERM U, Orsay, France. [email protected].
³⁷ Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany. [email protected].
³⁸ Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany, and DKTK, partner site Essen/Düsseldorf, Düsseldorf, Germany. [email protected].
³⁹ Institute of Neuropathology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany, DKTK, partner site Essen/Düsseldorf, Düsseldorf, Germany. [email protected].

^# Contributed equally.

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.

Publication types

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

MeSH terms

Animals
Carrier Proteins / metabolism
Cell Line, Tumor
Cell Proliferation
Cerebellar Neoplasms* / genetics
Dyneins / metabolism
Gene Expression Regulation, Neoplastic
Hedgehog Proteins / genetics
Hedgehog Proteins / metabolism
Humans
Medulloblastoma* / genetics
Membrane Glycoproteins / metabolism
Mice
MicroRNAs* / genetics
RNA, Long Noncoding* / genetics

Substances

Carrier Proteins
HHIP protein, human
Hedgehog Proteins
Hhip protein, mouse
Membrane Glycoproteins
MicroRNAs
RNA, Long Noncoding
SHH protein, human
Shh protein, mouse
Dyneins

Grants and funding

R01 AR054780/AR/NIAMS NIH HHS/United States