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RSK1 modulates the translatome of glioblastoma cells in an isoform-specific manner

ABSTRACT: The p90 ribosomal S6 kinase (RSK) family, downstream targets of Ras/ERK signaling, encompass four human isoforms (RSK1-4). Glioblastoma (GBM) predominantly expresses RSK1 and RSK2. Notably, RSK1 is markedly upregulated in a subset of GBMs associated with dismal prognosis and immune infiltration, whereas RSK2 expression remains consistent across cases. We verified that GBM-derived cell lines recapitulate RSK isoform expression profiles and estimated their stoichiometry. Through the generation of RSK1 and RSK2 knockout (RSK1KO and RSK2KO) as well as double knockout (DKO) GBM cells, we investigated isoform-specific functions of RSK. Surprisingly, contrary to conventional belief, we found that mTORC1 is not activated by RSK isoforms. Instead, eIF4B phosphorylation at S422 was RSK-dependent rather than mTORC1/S6K-dependent, with RSK1 exerting a more pronounced effect. Intriguingly, RSK1 and RSK2 displayed differential effects on translation, with RSK1 maintaining translation of specific mRNAs under conditions of reduced overall translation due to mTORC1 inhibition, unlike RSK2. Finally, we verified that while the translatome of RSK1KO cells show a downregulation of mRNAs affecting cell cycle, DNA replication and repair, RSK2 depletion impacted mitochondrial and respiratory genes. Notably, DKO cells exhibited compounded phenotypes, underscoring the existence of isoform-specific gene regulation programs orchestrated by RSK. Collectively, our findings offer mechanistic insights crucial for unraveling the role of RSK1 in GBMs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE263893 | GEO | 2025/06/25

REPOSITORIES: GEO

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Project description:The p90 ribosomal S6 kinase (RSK) family, a downstream target of Ras/extracellular signal-regulated kinase (ERK) signaling, can mediate cross-talk with the mammalian target of rapamycin complex 1 (mTORC1) pathway. As RSK connects two oncogenic pathways in gliomas, we investigated the protein levels of the RSK isoforms RSK1-4 in non-tumoral brain (NB) and grade I-IV gliomas. RSK4 expression was not detected in any brain tissues, whereas RSK3 expression was very low, with GBMs demonstrating the lowest RSK3 protein levels. When compared to NB or low-grade gliomas (LGG), a group of glioblastomas (RSK1hi) that excluded long-survivor cases expressed higher levels of RSK1. No difference was observed in RSK2 median-expression levels among NB and gliomas; however, high levels of RSK2 in glioblastomas (GBM) were associated with worse survival. RSK1hi and, to a lesser extent, RSK2hi GBMs, showed higher levels of phosphorylated RSK, which indicates RSK activation. Transcriptome analysis indicated that most RSK1hi GBMs belonged to the mesenchymal subtype, and RSK1 expression strongly correlated with gene expression signature of immune infiltrates, in particular of activated-natural killer cells and M2 macrophages. In an independent cohort, we confirmed that RSK1hi GBMs exclude long-survivors, and RSK1 expression was associated with high protein levels of the mesenchymal subtype marker LAPTM5, as well as with high expression of CD68, which indicated the presence of infiltrating immune cells. An RSK1 signature was obtained based on differentially expressed mRNAs and validated in public glioma datasets. Enrichment of RSK1 signature followed glioma progression, recapitulating RSK1 protein expression, and was associated with worse survival not only in GBM but also in LGG. In conclusion, both RSK1 and RSK2 associate with glioma malignity, but displaying isoform-specific peculiarities. The progression-dependent expression and association with immune infiltration, suggests RSK1 as a potential progression marker and therapeutic target for gliomas.

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RSK1 modulates the translatome of glioblastoma cells in an isoform-specific manner

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