The Expression of the Cancer-Associated lncRNA Snhg15 Is Modulated by EphrinA5-Induced Signaling

Abstract

The Eph receptor tyrosine kinases and their respective ephrin-ligands are an important family of membrane receptors, being involved in developmental processes such as proliferation, migration, and in the formation of brain cancer such as glioma. Intracellular signaling pathways, which are activated by Eph receptor signaling, are well characterized. In contrast, it is unknown so far whether ephrins modulate the expression of lncRNAs, which would enable the transduction of environmental stimuli into our genome through a great gene regulatory spectrum. Applying a combination of functional in vitro assays, RNA sequencing, and qPCR analysis, we found that the proliferation and migration promoting stimulation of mouse cerebellar granule cells (CB) with ephrinA5 diminishes the expression of the cancer-related lncRNA Snhg15. In a human medulloblastoma cell line (DAOY) ephrinA5 stimulation similarly reduced SNHG15 expression. Computational analysis identified triple-helix-mediated DNA-binding sites of Snhg15 in promoters of genes found up-regulated upon ephrinA5 stimulation and known to be involved in tumorigenic processes. Our findings propose a crucial role of Snhg15 downstream of ephrinA5-induced signaling in regulating gene transcription in the nucleus. These findings could be potentially relevant for the regulation of tumorigenic processes in the context of glioma.

NMR-Guided Design of Potent and Selective EphA4 Agonistic Ligands

“…The bidirectional signaling mediated by ephrinA5 and EphA4 also offers other possible therapeutic opportunities. For example, ephrinA5 mimetics, like 150D4 , could find applications also in oncology, including glioma and colon cancers, − where ephrinA5 was found to act as a tumor suppressor, interfering with EGFR. Unlike ephrinA5, 150D4 is more selective for the EphA4 subtype, and being a synthetic agent, it is readily available for translation into a therapeutic agent.…”

EphrinA5 regulates cell motility by modulating the targeting of DNMT1 to theNcam1promoter via lncRNA/DNA triplex formation

“…Cerebellar granule (CB) cells (Fossale et al, 2004) were cultured as previously described (Pensold et al, 2021). Briefly, CB cells were incubated in Dulbecco’s modified Eagle medium (DMEM) with high glucose (#11965084, Gibco), supplemented with 10% fetal bovine serum (FBS) (#S1810, Biowest), 1× GlutaMAX™lJ (#35050038, Thermo Scientific) and 24 mM KCl at 33LJ, 5% CO 2 and 95% relative humidity.…”

“…For Adamts14, the sequence-based predictions (method described in Pensold et al, 2021; sequences presented in Supplementary Table S2) suggested two slightly different alternatives for the 15-nucleotide binding mode, which were used to generate the two models, Adamts14 -1 and Adamts14 -2. For Ncam1, a 15-nucleotide sequence ( Ncam1 ) as well as an extended sequence ( Ncam1 -ext) with additional base pairs (see Supplementary Table S2) were chosen.…”

“…We recently provided evidence that the stimulation of cell culture models for medulloblastoma, namely immortalized cerebellar granule (CB) as well as DAOY cells, with ephrinA5, a known tumor suppressor in glioma, has the potential to alter the expression of protein-coding genes and lncRNAs, such as the cancer-relevant lncRNA SNHG15 (Pensold et al, 2021). In addition to SNHG15, abnormal expression of diverse lncRNAs has been implicated in glioma and medulloblastoma molecular pathology (Laneve et al, 2019; Stackhouse et al, 2020).…”

Long noncoding RNA SNHG15: A promising target in human cancers

“…Ultimately in clear cell renal cell carcinoma (ccRCC), DNA hypomethylation might play a notable role in elevating SNHG15 transcription by substantially modulating its expression level. In the human medulloblastoma cell line DAOY, SNHG15 was modulated by EphrinA5-induced signal transduction, with EphrinA5 stimulation significantly reduced SNHG15 expression which might be relevant for the regulation of tumorigenic processes in the context of glioma ( 126 ).…”