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 () and Marc Remke ()
Additional contact information
Jasmin Bartl: Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf
Marco Zanini: Institut Curie, PSL Research University, CNRS UMR, INSERM
Flavia Bernardi: Institut Curie, PSL Research University, CNRS UMR, INSERM
Antoine Forget: Institut Curie, PSL Research University, CNRS UMR, INSERM
Lena Blümel: Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf
Julie Talbot: Institut Curie, PSL Research University, CNRS UMR, INSERM
Daniel Picard: Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf
Nan Qin: Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf
Gabriele Cancila: Institut Curie, PSL Research University, CNRS UMR, INSERM
Qingsong Gao: St Jude Children’s Research Hospital
Soumav Nath: Heinrich Heine University
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
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
Viktoria Marquardt: Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf
Hua Yu: Institut Curie, PSL Research University, CNRS UMR, INSERM
Judith Souphron: Institut Curie, PSL Research University, CNRS UMR, INSERM
Mascha Korsch: Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf
Christina Mölders: Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf
Daniel Berger: Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf
Sarah Göbbels: Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf
Frauke-Dorothee Meyer: Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf
Björn Scheffler: partner site University Hospital Essen
Barak Rotblat: Ben-Gurion University of the Negev
Sven Diederichs: University of Freiburg, DKTK, partner site Freiburg
Vijay Ramaswamy: The Hospital for Sick Children
Hiromishi Suzuki: The Hospital for Sick Children
Anthony Oro: Stanford University School of Medicine
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
Gerhard Steger: Heinrich Heine University
Alexander Buell: Technical University of Denmark
Marcel Kool: Hopp Children´s Cancer Center (KiTZ)
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)
Paul A. Northcott: St Jude Children’s Research Hospital
Michael D. Taylor: 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
Marc Remke: Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31574-z

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