The HHIP-AS1 lncRNA promotes tumorigenicity through stabilization of dynein complex 1 in human SHH-driven tumors
-
Published:2022-07-13
Issue:1
Volume:13
Page:
-
ISSN:2041-1723
-
Container-title:Nature Communications
-
language:en
-
Short-container-title:Nat Commun
Author:
Bartl JasminORCID, Zanini Marco, Bernardi Flavia, Forget Antoine, Blümel Lena, Talbot Julie, Picard Daniel, Qin Nan, Cancila Gabriele, Gao Qingsong, Nath Soumav, Koumba Idriss Mahoungou, Wolter Marietta, Kuonen François, Langini MaikeORCID, Beez Thomas, Munoz Christopher, Pauck David, Marquardt Viktoria, Yu Hua, Souphron Judith, Korsch MaschaORCID, Mölders Christina, Berger Daniel, Göbbels Sarah, Meyer Frauke-Dorothee, Scheffler BjörnORCID, Rotblat Barak, Diederichs SvenORCID, Ramaswamy VijayORCID, Suzuki HiromishiORCID, Oro AnthonyORCID, Stühler Kai, Stefanski Anja, Fischer UteORCID, Leprivier Gabriel, Willbold Dieter, Steger Gerhard, Buell AlexanderORCID, Kool Marcel, Lichter Peter, Pfister Stefan M.ORCID, Northcott Paul A.ORCID, Taylor Michael D.ORCID, Borkhardt ArndtORCID, Reifenberger Guido, Ayrault OlivierORCID, Remke MarcORCID
Abstract
AbstractMost 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.
Funder
Elterinitiative Kinderkrebsklinik e.V., UKD, Dusseldorf, Germany Ministère Français de l’Enseignement Supérieur et de la Recherche Forschungskommission of University Dusseldorf, Germany St. Baldrick's Foundation Robert J. Arceci Innovation Award ITMO Cancer AVIESAN Robert J. Arceci Innovation Award Deutsche Krebshilfe Deutsche Forschungsgemeinschaft Pediatric Brain Tumor Foundation
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference64 articles.
1. Tan, I. L. et al. Lateral cerebellum is preferentially sensitive to high sonic hedgehog signaling and medulloblastoma formation. Proc. Natl Acad. Sci. USA 115, 3392–3397 (2018). 2. Reifenberger, J. et al. Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas. Br. J. Dermatol 152, 43–51 (2005). 3. Stewart, E. et al. Identification of therapeutic targets in rhabdomyosarcoma through integrated genomic, epigenomic, and proteomic analyses. Cancer Cell 34, 411–426.e419 (2018). 4. Johann, P. D. et al. Atypical teratoid/rhabdoid tumors are comprised of three epigenetic subgroups with distinct enhancer landscapes. Cancer Cell 29, 379–393 (2016). 5. Liu, K. W., Pajtler, K. W., Worst, B. C., Pfister, S. M. & Wechsler-Reya, R. J. Molecular mechanisms and therapeutic targets in pediatric brain tumors. Sci. Signal. https://doi.org/10.1126/scisignal.aaf7593 (2017).
Cited by
18 articles.
订阅此论文施引文献
订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献
|
|