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.
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 Gao  10 ,  Soumav Nath  11  12 ,  Idriss Mahoungou Koumba  8 ,  Marietta Wolter  9 ,  François Kuonen  13  14 ,  Maike Langini  15 ,  Thomas Beez  16 ,  Christopher Munoz  16 ,  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 Scheffler  17 ,  Barak Rotblat  18  19 ,  Sven Diederichs  20  21 ,  Vijay Ramaswamy  22  23 ,  Hiromishi Suzuki  22 ,  Anthony Oro  13  24 ,  Kai Stühler  25 ,  Anja Stefanski  25 ,  Ute Fischer  8 ,  Gabriel Leprivier  9 ,  Dieter Willbold  11  12 ,  Gerhard Steger  11 ,  Alexander Buell  26 ,  Marcel Kool  27  28  29 ,  Peter Lichter  30 ,  Stefan M Pfister  27  28  31 ,  Paul A Northcott  10 ,  Michael D Taylor  22  32  33  34 ,  Arndt Borkhardt  8 ,  Guido Reifenberger  9 ,  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.
PMID: 35831316 DOI: 10.1038/s41467-022-31574-z
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.

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