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

• DOI: 10.1038/s41467-022-31574-z
• Publication Date: 2022-07-13T21:29:08Z
• Authors: Jasmin Bartl; Marco Zanini; Flavia Bernardi; Antoine Forget; Lena Blümel; Julie Talbot; Daniel Picard; Nan Qin; Gabriele Cancila; Qingsong Gao; Soumav Nath; Idriss Mahoungou ...; 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 M...; 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
• Keywords: 0301 basic medicine; Science; Medizin; 610; 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; Article; Mice; 03 medical and health sciences; Cell Line, Tumor; [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology; Animals; Humans; Hedgehog Proteins; /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being; name=SDG 3 - Good Health and Well-being; Cerebellar Neoplasms; Cell Proliferation; Membrane Glycoproteins; Q; Dyneins; 3. Good health; Gene Expression Regulation, Neoplastic; MicroRNAs; RNA, Long Noncoding; Carrier Proteins; info:eu-repo/classification/ddc/500; Medulloblastoma

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