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; Marc Remke

doi:10.1038/s41467-022-31574-z

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 YuJudith 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, Marc Remke

Ben-Gurion University of the Negev

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	4061
Pages (from-to)	4061
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-31574-z
State	Published - 13 Jul 2022

Keywords

Animals
Carrier Proteins/metabolism
Cell Line, Tumor
Cell Proliferation
Cerebellar Neoplasms/genetics
Dyneins/metabolism
Gene Expression Regulation, Neoplastic
Hedgehog Proteins/genetics
Humans
Medulloblastoma/genetics
Membrane Glycoproteins/metabolism
Mice
MicroRNAs/genetics
RNA, Long Noncoding/genetics

All Science Journal Classification (ASJC) codes

General Chemistry
General
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-022-31574-z

Cite this

Bartl, J., Zanini, M., Bernardi, F., Forget, A., Blümel, L., Talbot, J., Picard, D., Qin, N., Cancila, G., Gao, Q., Nath, S., Koumba, I. M., Wolter, M., Kuonen, F., Langini, M., Beez, T., Munoz, C., Pauck, D., Marquardt, V., ... Remke, M. (2022). The HHIP-AS1 lncRNA promotes tumorigenicity through stabilization of dynein complex 1 in human SHH-driven tumors. Nature Communications, 13(1), 4061. Article 4061. https://doi.org/10.1038/s41467-022-31574-z

@article{1a2a1f0f3974403d975d219926c5e0ab,

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

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.",

keywords = "Animals, Carrier Proteins/metabolism, Cell Line, Tumor, Cell Proliferation, Cerebellar Neoplasms/genetics, Dyneins/metabolism, Gene Expression Regulation, Neoplastic, Hedgehog Proteins/genetics, Humans, Medulloblastoma/genetics, Membrane Glycoproteins/metabolism, Mice, MicroRNAs/genetics, RNA, Long Noncoding/genetics",

author = "Jasmin Bartl and Marco Zanini and Flavia Bernardi and Antoine Forget and Lena Bl{\"u}mel and Julie Talbot and Daniel Picard and Nan Qin and Gabriele Cancila and Qingsong Gao and Soumav Nath and Koumba, {Idriss Mahoungou} and Marietta Wolter and Fran{\c c}ois Kuonen and Maike Langini and Thomas Beez and Christopher Munoz and David Pauck and Viktoria Marquardt and Hua Yu and Judith Souphron and Mascha Korsch and Christina M{\"o}lders and Daniel Berger and Sarah G{\"o}bbels and Meyer, {Frauke Dorothee} and Bj{\"o}rn Scheffler and Barak Rotblat and Sven Diederichs and Vijay Ramaswamy and Hiromishi Suzuki and Anthony Oro and Kai St{\"u}hler and Anja Stefanski and Ute Fischer and Gabriel Leprivier and Dieter Willbold and Gerhard Steger and Alexander Buell and Marcel Kool and Peter Lichter and Pfister, {Stefan M.} and Northcott, {Paul A.} and Taylor, {Michael D.} and Arndt Borkhardt and Guido Reifenberger and Olivier Ayrault and Marc Remke",

note = "{\textcopyright} 2022. The Author(s).",

year = "2022",

month = jul,

day = "13",

doi = "10.1038/s41467-022-31574-z",

language = "الإنجليزيّة",

volume = "13",

pages = "4061",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Bartl, J, Zanini, M, Bernardi, F, Forget, A, Blümel, L, Talbot, J, Picard, D, Qin, N, Cancila, G, Gao, Q, Nath, S, Koumba, IM, Wolter, M, Kuonen, F, Langini, M, Beez, T, Munoz, C, Pauck, D, Marquardt, V, Yu, H, Souphron, J, Korsch, M, Mölders, C, Berger, D, Göbbels, S, Meyer, FD, Scheffler, B, Rotblat, B, Diederichs, S, Ramaswamy, V, Suzuki, H, Oro, A, Stühler, K, Stefanski, A, Fischer, U, Leprivier, G, Willbold, D, Steger, G, Buell, A, Kool, M, Lichter, P, Pfister, SM, Northcott, PA, Taylor, MD, Borkhardt, A, Reifenberger, G, Ayrault, O & Remke, M 2022, 'The HHIP-AS1 lncRNA promotes tumorigenicity through stabilization of dynein complex 1 in human SHH-driven tumors', Nature Communications, vol. 13, no. 1, 4061, pp. 4061. https://doi.org/10.1038/s41467-022-31574-z

TY - JOUR

T1 - The HHIP-AS1 lncRNA promotes tumorigenicity through stabilization of dynein complex 1 in human SHH-driven tumors

AU - Bartl, Jasmin

AU - Zanini, Marco

AU - Bernardi, Flavia

AU - Forget, Antoine

AU - Blümel, Lena

AU - Talbot, Julie

AU - Picard, Daniel

AU - Qin, Nan

AU - Cancila, Gabriele

AU - Gao, Qingsong

AU - Nath, Soumav

AU - Koumba, Idriss Mahoungou

AU - Wolter, Marietta

AU - Kuonen, François

AU - Langini, Maike

AU - Beez, Thomas

AU - Munoz, Christopher

AU - Pauck, David

AU - Marquardt, Viktoria

AU - Yu, Hua

AU - Souphron, Judith

AU - Korsch, Mascha

AU - Mölders, Christina

AU - Berger, Daniel

AU - Göbbels, Sarah

AU - Meyer, Frauke Dorothee

AU - Scheffler, Björn

AU - Rotblat, Barak

AU - Diederichs, Sven

AU - Ramaswamy, Vijay

AU - Suzuki, Hiromishi

AU - Oro, Anthony

AU - Stühler, Kai

AU - Stefanski, Anja

AU - Fischer, Ute

AU - Leprivier, Gabriel

AU - Willbold, Dieter

AU - Steger, Gerhard

AU - Buell, Alexander

AU - Kool, Marcel

AU - Lichter, Peter

AU - Pfister, Stefan M.

AU - Northcott, Paul A.

AU - Taylor, Michael D.

AU - Borkhardt, Arndt

AU - Reifenberger, Guido

AU - Ayrault, Olivier

AU - Remke, Marc

PY - 2022/7/13

Y1 - 2022/7/13

N2 - 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.

AB - 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.

KW - Animals

KW - Carrier Proteins/metabolism

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Cerebellar Neoplasms/genetics

KW - Dyneins/metabolism

KW - Gene Expression Regulation, Neoplastic

KW - Hedgehog Proteins/genetics

KW - Humans

KW - Medulloblastoma/genetics

KW - Membrane Glycoproteins/metabolism

KW - Mice

KW - MicroRNAs/genetics

KW - RNA, Long Noncoding/genetics

UR - http://www.scopus.com/inward/record.url?scp=85133985420&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-31574-z

DO - 10.1038/s41467-022-31574-z

M3 - مقالة

C2 - 35831316

SN - 2041-1723

VL - 13

SP - 4061

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4061

ER -

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

Abstract

Keywords

All Science Journal Classification (ASJC) codes

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this