Dataset Information

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.

SUBMITTER: Bartl J

PROVIDER: S-EPMC9279496 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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

Bartl Jasmin J Zanini Marco M Bernardi Flavia F Forget Antoine A Blümel Lena L Talbot Julie J Picard Daniel D Qin Nan N Cancila Gabriele G Gao Qingsong Q Nath Soumav S Koumba Idriss Mahoungou IM Wolter Marietta M Kuonen François F Langini Maike M Beez Thomas T Munoz Christopher C Pauck David D Marquardt Viktoria V Yu Hua H Souphron Judith J Korsch Mascha M Mölders Christina C Berger Daniel D Göbbels Sarah S Meyer Frauke-Dorothee FD Scheffler Björn B Rotblat Barak B Diederichs Sven S Ramaswamy Vijay V Suzuki Hiromishi H Oro Anthony A Stühler Kai K Stefanski Anja A Fischer Ute U Leprivier Gabriel G Willbold Dieter D Steger Gerhard G Buell Alexander A Kool Marcel M Lichter Peter P Pfister Stefan M SM Northcott Paul A PA Taylor Michael D MD Borkhardt Arndt A Reifenberger Guido G Ayrault Olivier O Remke Marc M

Nature communications 20220713 1

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 a ...[more]

PMID: 35831316

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Project description:GBM (Glioblastoma multiform) is the most malignant tumor type of the central nervous system and has poor diagnostic and clinical outcomes. LncRNAs (Long non-coding RNAs) have been reported to participate in multiple biological and pathological processes, but their underlying mechanism remains poorly understood. Here, we aimed to explore the role of the lncRNA HAS2-AS1 (HAS2 antisense RNA 1) in GBM. GSE103227 was analyzed, and qRT-PCR was performed to measure the expression of HAS2-AS1 in GBM. FISH (Fluorescence in situ hybridization) was performed to verify the localization of HAS2-AS1. The interaction between HAS2-AS1 and miR-137 (microRNA-137) was predicted by LncBook and miRcode followed by dual-luciferase reporter assays, and the relationships among HAS2-AS1, miR-137 and LSD1 (lysine-specific demethylase 1) were assessed by WB (western blot) and qRT-PCR. Colony formation and CCK-8 (cell counting kit-8) assays were performed as functional tests. In vivo, nude mice were used to confirm the function of HAS2-AS1. HAS2-AS1 expression was upregulated in GBM cell lines, and HAS2-AS1 was localized mainly in the cytoplasm. In vitro, high HAS2-AS1 expression promoted proliferation, and knockdown of HAS2-AS1 significantly inhibited proliferation. Furthermore, HAS2-AS1 functioned as a ceRNA (competing endogenous RNA) of miR-137, leading to the disinhibition of its downstream target LSD1. The miR-137 level was downregulated by HAS2-AS1 overexpression and upregulated by HAS2-AS1 knockdown. In a subsequent study, LSD1 expression was negatively regulated by miR-137, while miR-137 reversed the LSD1 expression levels caused by HAS2-AS1. These results were further supported by the nude mouse tumorigenesis experiment; compared with xenografts with high HAS2-AS1 expression, the group with low levels of HAS2-AS1 exhibited suppressed proliferation and better survival. We conclude that lncRNA HAS2-AS1 promotes proliferation by functioning as a miR-137 decoy to increase LSD1 levels and thus might be a possible biomarker for GBM.

Dataset Information

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

Publications

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

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