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

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Listed:
  • Jasmin Bartl

    (Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf
    Heinrich Heine University, Düsseldorf, Germany, and DKTK, partner site Essen/Düsseldorf
    Heinrich Heine University, Düsseldorf, Germany, DKTK, partner site Essen/Düsseldorf
    Institute of Zoology University of Hamburg)

  • Marco Zanini

    (Institut Curie, PSL Research University, CNRS UMR, INSERM
    Université Paris Sud, Université Paris-Saclay, CNRS UMR, INSERM U)

  • Flavia Bernardi

    (Institut Curie, PSL Research University, CNRS UMR, INSERM
    Université Paris Sud, Université Paris-Saclay, CNRS UMR, INSERM U)

  • Antoine Forget

    (Institut Curie, PSL Research University, CNRS UMR, INSERM
    Université Paris Sud, Université Paris-Saclay, CNRS UMR, INSERM U)

  • Lena Blümel

    (Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf
    Heinrich Heine University, Düsseldorf, Germany, and DKTK, partner site Essen/Düsseldorf
    Heinrich Heine University, Düsseldorf, Germany, DKTK, partner site Essen/Düsseldorf)

  • Julie Talbot

    (Institut Curie, PSL Research University, CNRS UMR, INSERM
    Université Paris Sud, Université Paris-Saclay, CNRS UMR, INSERM U)

  • Daniel Picard

    (Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf
    Heinrich Heine University, Düsseldorf, Germany, and DKTK, partner site Essen/Düsseldorf
    Heinrich Heine University, Düsseldorf, Germany, DKTK, partner site Essen/Düsseldorf)

  • Nan Qin

    (Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf
    Heinrich Heine University, Düsseldorf, Germany, and DKTK, partner site Essen/Düsseldorf
    Heinrich Heine University, Düsseldorf, Germany, DKTK, partner site Essen/Düsseldorf)

  • Gabriele Cancila

    (Institut Curie, PSL Research University, CNRS UMR, INSERM
    Université Paris Sud, Université Paris-Saclay, CNRS UMR, INSERM U)

  • Qingsong Gao

    (St Jude Children’s Research Hospital)

  • Soumav Nath

    (Heinrich Heine University
    IBI- (Strukturbiochemie) and JuStruct, Forschungszentrum Jülich)

  • Idriss Mahoungou Koumba

    (Heinrich Heine University, Düsseldorf, Germany, and DKTK, partner site Essen/Düsseldorf)

  • Marietta Wolter

    (Heinrich Heine University, Düsseldorf, Germany, DKTK, partner site Essen/Düsseldorf)

  • François Kuonen

    (Stanford University School of Medicine
    Lausanne University Hospital Center, CH- Lausanne)

  • Maike Langini

    (Heinrich Heine University)

  • Thomas Beez

    (Heinrich Heine University)

  • Christopher Munoz

    (Heinrich Heine University)

  • David Pauck

    (Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf
    Heinrich Heine University, Düsseldorf, Germany, and DKTK, partner site Essen/Düsseldorf
    Heinrich Heine University, Düsseldorf, Germany, DKTK, partner site Essen/Düsseldorf)

  • Viktoria Marquardt

    (Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf
    Heinrich Heine University, Düsseldorf, Germany, and DKTK, partner site Essen/Düsseldorf
    Heinrich Heine University, Düsseldorf, Germany, DKTK, partner site Essen/Düsseldorf)

  • Hua Yu

    (Institut Curie, PSL Research University, CNRS UMR, INSERM
    Université Paris Sud, Université Paris-Saclay, CNRS UMR, INSERM U)

  • Judith Souphron

    (Institut Curie, PSL Research University, CNRS UMR, INSERM
    Université Paris Sud, Université Paris-Saclay, CNRS UMR, INSERM U)

  • Mascha Korsch

    (Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf
    Heinrich Heine University, Düsseldorf, Germany, and DKTK, partner site Essen/Düsseldorf
    Heinrich Heine University, Düsseldorf, Germany, DKTK, partner site Essen/Düsseldorf)

  • Christina Mölders

    (Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf
    Heinrich Heine University, Düsseldorf, Germany, and DKTK, partner site Essen/Düsseldorf
    Heinrich Heine University, Düsseldorf, Germany, DKTK, partner site Essen/Düsseldorf)

  • Daniel Berger

    (Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf
    Heinrich Heine University, Düsseldorf, Germany, and DKTK, partner site Essen/Düsseldorf
    Heinrich Heine University, Düsseldorf, Germany, DKTK, partner site Essen/Düsseldorf)

  • Sarah Göbbels

    (Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf
    Heinrich Heine University, Düsseldorf, Germany, and DKTK, partner site Essen/Düsseldorf
    Heinrich Heine University, Düsseldorf, Germany, DKTK, partner site Essen/Düsseldorf)

  • Frauke-Dorothee Meyer

    (Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf
    Heinrich Heine University, Düsseldorf, Germany, and DKTK, partner site Essen/Düsseldorf
    Heinrich Heine University, Düsseldorf, Germany, DKTK, partner site Essen/Düsseldorf)

  • Björn Scheffler

    (partner site University Hospital Essen)

  • Barak Rotblat

    (Ben-Gurion University of the Negev
    The National Institute for Biotechnology in the Negev)

  • Sven Diederichs

    (University of Freiburg, DKTK, partner site Freiburg
    Division of RNA Biology & Cancer, DKFZ)

  • Vijay Ramaswamy

    (The Hospital for Sick Children
    The Hospital for Sick Children)

  • Hiromishi Suzuki

    (The Hospital for Sick Children)

  • Anthony Oro

    (Stanford University School of Medicine
    Stanford University)

  • Kai Stühler

    (Heinrich Heine University)

  • Anja Stefanski

    (Heinrich Heine University)

  • Ute Fischer

    (Heinrich Heine University, Düsseldorf, Germany, and DKTK, partner site Essen/Düsseldorf)

  • Gabriel Leprivier

    (Heinrich Heine University, Düsseldorf, Germany, DKTK, partner site Essen/Düsseldorf)

  • Dieter Willbold

    (Heinrich Heine University
    IBI- (Strukturbiochemie) and JuStruct, Forschungszentrum Jülich)

  • Gerhard Steger

    (Heinrich Heine University)

  • Alexander Buell

    (Technical University of Denmark)

  • Marcel Kool

    (Hopp Children´s Cancer Center (KiTZ)
    Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
    Princess Máxima Center for Pediatric Oncology)

  • Peter Lichter

    (Division of Molecular Genetics, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), and National Center for Tumor Diseases (NCT))

  • Stefan M. Pfister

    (Hopp Children´s Cancer Center (KiTZ)
    Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)
    Heidelberg University Hospital)

  • Paul A. Northcott

    (St Jude Children’s Research Hospital)

  • Michael D. Taylor

    (The Hospital for Sick Children
    The Hospital for Sick Children
    University of Toronto
    The Hospital for Sick Children)

  • Arndt Borkhardt

    (Heinrich Heine University, Düsseldorf, Germany, and DKTK, partner site Essen/Düsseldorf)

  • Guido Reifenberger

    (Heinrich Heine University, Düsseldorf, Germany, DKTK, partner site Essen/Düsseldorf)

  • Olivier Ayrault

    (Institut Curie, PSL Research University, CNRS UMR, INSERM
    Université Paris Sud, Université Paris-Saclay, CNRS UMR, INSERM U)

  • Marc Remke

    (Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf
    Heinrich Heine University, Düsseldorf, Germany, and DKTK, partner site Essen/Düsseldorf
    Heinrich Heine University, Düsseldorf, Germany, DKTK, partner site Essen/Düsseldorf)

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.

Suggested Citation

  • 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 & Mariet, 2022. "The HHIP-AS1 lncRNA promotes tumorigenicity through stabilization of dynein complex 1 in human SHH-driven tumors," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31574-z
    DOI: 10.1038/s41467-022-31574-z
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