NSD1 expression correlates with Akt/mTORC1 pathway activity in head and neck squamous cell carcinoma

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Abstract
Introduction. Histone methyltransferase NSD1 is often inactivated in head and neck squamous cell carcinoma. Loss of NSD1 is associated with improved prognosis in HPV (human papilloma virus) negative cancer. However, data on the signaling pathways regulated by NSD1 are limited. Aim. Validation and systemic assessment of reproducibility of the NSD1-Akt/mTORC1 axis based on integrative analysis of open transcriptomic and proteomic data from cell lines and samples of head and neck squamous cell carcinoma. Materials and methods. Systemic analysis was performed of the connection between NSD1 and Akt/mTORC1 signaling pathway using open transcriptomic and proteomic data (panel of squamous cell carcinoma cell lines on the DepMap portal and clinical cohorts from the The Cancer Genome Atlas (TCGA)). Pathway activity was evaluated using ssGSEA/GSEA (single-sample Gene Set Enrichment Analysis), proteomic activity – using protein expression data obtained with Reverse Phase Protein Array (RPPA), statistical significance – using standard correlation and nonparametric tests. Results. In the cell line panel, elevated NSD1 expression correlated with stronger PI3K/AKT/mTOR transcription signature and increased phosphorylation of the key pathway components according to RPPA data. Similar correlation was observed in patient tumor samples. Data on isogenic cell lines with NSD1 knockout demonstrated decreased expression of mTORC1 target genes. Conclusion. Reproducible correlation between NSD1 level and Akt/mTORC1 signaling pathway activity in head and neck cancer was established. However, additional confirmation of the NSD1 role in regulation of the Akt/mTORC1 pathways requires in vitro and in vivo investigation of expression and phosphorylation of protein components of this cascade, as well as functional experiments to evaluate proliferation, survival and drug sensitivity of head and neck cancer cells. Clinical significance of the established correlation in the context of disease progression requires further verification.

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