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

Bartl, Jasmin; Zanini, M.; 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, Maike; Beez, Thomas; Munoz, Christopher; Pauck, David; Marquardt, Viktoria; Yu, Hua; Souphron, Judith; Korsch, Mascha; Mölders, Christina; Berger, Daniel; Göbbels, Sarah; Meyer, Frank; Scheffler, Björn; Diederichs, Sven; Ramaswamy, Vijay; Suzuki, Hiromichi; Oro, Anthony E.; Stefanski, Anja; Fischer, Ute; Leprivier, Gabriel; Willbold, Dieter; Steger, Gerhard; Buell, Alexander K.; Kool, Marcel; Lichter, Peter; Pfister, Stefan M.; Northcott, Paul A.; Taylor, Michael D.; Reifenberger, Guido; Ayrault, Olivier; Remke, Marc

doi:10.1038/s41467-022-31574-z

Cited by 21 publications

(26 citation statements)

References 63 publications

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“…At the transcriptional level, a possible mechanism is that antisense lncRNAs share a promoter with nearby genes, thereby suffering from similar transcriptional regulation. Bartl and colleagues have reported that lncRNA HHIP-AS1 and HHIP shared promoters, and this promoter activity was negatively regulated by DNA methylation [33]. Herein, we also found that ELF3-AS1 and ELF3 genes shared the same promoter, which makes them both under the repression of SNAI2 and SNAI1 (Fig 9A).…”

Section: Discussionsupporting

confidence: 67%

LncRNA ELF3-AS1 inhibits gastric cancer by forming a negative feedback loop with SNAI2 and regulates ELF3 mRNA stability via interacting with ILF2/ILF3 complex

Shen

Zhang

et al. 2022

J Exp Clin Cancer Res

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Background The biological function of lncRNA ELF3-AS1 remains largely unknown in cancers. The cause of SNAI2 overexpression in tumor metastasis remains largely unclear. The molecular mechanisms underlying the high co-expression of antisense lncRNAs and adjacent protein-coding genes remains unclear. Methods RNA-seq, CHIP and dual-luciferase reporter assay were performed to identify lncRNAs regulated by SNAI2. MicroRNA-seq and RNA-seq studies were conducted to reveal the biological function of ELF3-AS1 in GC. RNA pulldown and CHIRP assays were conducted to identify the protein that interacts with ELF3-AS1. Results A total of 123 lncRNAs were identified to be regulated by SNAI2 in GC by RNA sequencing. The ELF3 gene and antisense lncRNA ELF3-AS1 were both transcriptionally repressed by SNAI2 or SNAI1. Down-regulation of ELF3-AS1 and ELF3 predicted poor prognosis in GC. Nuclear localized lncRNA ELF3-AS1 negatively regulated GC cell cycle progression via suppressing G1/S transition and histone synthesis. ELF3-AS1 mainly inhibited GC metastasis by repressing SNAI2 signaling. Additionally, ELF3-AS1 modulated ELF3 mRNA stability by RNA-RNA interaction. The RNA duplexes formed by ELF3 mRNA and lncRNA ELF3-AS1 directly interacted with the double-stranded RNA (dsRNA) binding protein complex ILF2/ILF3 (NF45/NF90). In turn, the ILF2/ILF3 complex dynamically regulated the expression of ELF3-AS1 and ELF3 by affecting the dsRNA stability. Conclusions The SNAI2-ELF3-AS1 feedback loop regulates ELF3 expression at transcriptional and post-transcriptional levels and drives gastric cancer metastasis by maintaining SNAI2 overexpression. The ILF2/ILF3 complex plays a critical role in regulating dsRNA stability. In addition, our work provides a direct evidence that head-to-head antisense lncRNAs can share promoters with neighboring coding genes, which make their expression subject to similar transcriptional regulation, leading to high co-expression.

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Section: Discussionsupporting

confidence: 67%

LncRNA ELF3-AS1 inhibits gastric cancer by forming a negative feedback loop with SNAI2 and regulates ELF3 mRNA stability via interacting with ILF2/ILF3 complex

Shen

Zhang

et al. 2022

J Exp Clin Cancer Res

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“…This probably happens because HHIP-AS1 is actively transcribed from a SHH-responsive bidirectional promoter shared with the SHH signalling intermediate HHIP. In SHH-driven tumours, the knockdown of HHIP-AS1 induces mitotic spindle deregulation and the consequential reduction of tumorigenicity in vitro and in vivo [ 47 ] . Taken together, these data suggest HHIP-AS1 to be a suitable candidate for further functional studies to explore its possible role in enabling the pro-mitotic effects of SHH pathway activation in childhood T-ALL.…”

Section: Discussionmentioning

confidence: 99%

Specific lncRNA signatures discriminate childhood acute leukaemias: a pilot study

Buono¹,

Iside²,

Matteo

et al. 2022

Cancer Cell Int

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Background Long non-coding RNAs are RNAs longer than 200 bps that do not encode any proteins and are able to alter gene expression by acting on different steps of regulation, including DNA methylation and chromatin structure. They represent a class of biomarkers of crescent interest in the hematologic and oncologic fields. Recent studies showed that the expression levels of specific lncRNAs correlate with the prognosis of paediatric patients with Acute Lymphoblastic Leukaemia. Methods We used NGS approaches to analyse the transcriptome of 9 childhood B-ALL patients and 6 childhood T-ALL patients, in comparison with B and T healthy lymphocytes from cord blood. We validate our findings both ex vivo, in a different cohort of 10 B-ALL and 10 T-ALL patients, and in silico using public datasets. Results We characterised the lncRNA landscape for B-ALL, T-ALL, healthy B, and T cell progenitors. From the characterised signature, we selected candidate lncRNAs able to discriminate not only B-ALL and T-ALL from healthy subjects but also between the two types of leukaemia, and subsequently validated their potential as a diagnostic tool in an additional cohort of paediatric patients. We confirmed our finding with open access transcriptomic data, comparing ALL lncRNAs with AML lncRNA landscape as well. Finally, expression correlation analyses of T-ALL selected lncRNA biomarkers suggested a possible role in lymphocyte activation and the β-catenin signalling pathway for AC247036.1 and involvement in hedgehog signalling for HHIP-AS1. Conclusions Our work identified a lncRNA signature discriminating paediatric B-ALL and T-ALL from healthy subjects, between them and from AML. This study provides the keystone to future clinical studies determining the theragnostic value of the characterised long non coding transcriptome panorama in a clinical setting for childhood patient management.

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“…This probably happens because HHIP-AS1 is actively transcribed from a SHHresponsive bidirectional promoter shared with the SHH signalling intermediate HHIP. In SHH-driven tumours, the knockdown of HHIP-AS1 induces mitotic spindle deregulation and the consequential reduction of tumorigenicity in vitro and in vivo (43). Taken together, these data suggest HHIP-AS1 to be a suitable candidate for further functional studies to explore its possible role in enabling the pro-mitotic effects of SHH pathway activation in childhood T-ALL.…”

Section: Discussionmentioning

confidence: 83%

Specific lncRNA signatures discriminate childhood acute leukemias: a pilot study

Buono

Iside

Matteo

et al. 2022

Preprint

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BackgroundLong non-coding RNAs are RNAs longer than 200 bps that do not encode any proteins and are able to alter gene expression by acting on different steps of regulation, including DNA methylation and chromatin structure. They represent a class of biomarkers of crescent interest in the hematologic and oncologic fields. Recent studies showed that the expression levels of specific lncRNAs correlate with the prognosis of paediatric patients with Acute Lymphoblastic Leukaemia.MethodsWe used NGS approaches to analyse the transcriptome of 9 childhood B-ALL patients and 6 childhood T-ALL patients, in comparison with B and T healthy lymphocytes from cord blood. We validate our findings both ex vivo, in a different cohort of 10 B-ALL and 10 T-ALL patients, and in silico using public datasets.ResultsWe characterised the lncRNA landscape for B-ALL, T-ALL, healthy B, and T cell progenitors. From the characterised signature, we selected candidate lncRNAs able to discriminate not only B-ALL and T-ALL from healthy subjects but also between the two types of leukaemia, and subsequently validated their potential as a diagnostic tool in an additional cohort of paediatric patients. We confirmed our finding with open access transcriptomic data, comparing ALL lncRNAs with AML lncRNA landscape as well. Finally, expression correlation analyses of T-ALL selected lncRNA biomarkers suggested a possible role in lymphocyte activation and the β-catenin signalling pathway for AC247036.1 and involvement in hedgehog signalling for HHIP-AS1.ConclusionsOur work identified a lncRNA signature discriminating paediatric B-ALL and T-ALL from healthy subjects, between them and from AML. This study provides the keystone to future clinical studies determining the theragnostic value of the characterised long non coding transcriptome panorama in a clinical setting for childhood patient management.

show abstract

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

Cited by 21 publications

References 63 publications

LncRNA ELF3-AS1 inhibits gastric cancer by forming a negative feedback loop with SNAI2 and regulates ELF3 mRNA stability via interacting with ILF2/ILF3 complex

LncRNA ELF3-AS1 inhibits gastric cancer by forming a negative feedback loop with SNAI2 and regulates ELF3 mRNA stability via interacting with ILF2/ILF3 complex

Specific lncRNA signatures discriminate childhood acute leukaemias: a pilot study

Specific lncRNA signatures discriminate childhood acute leukemias: a pilot study

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