Bioinformatics analysis of PSAT1 loss identifies downstream pathways regulated in EGFR mutant NSCLC and a selective gene signature for predicting the risk of relapse

Biyik‑Sit,Rumeysa; Waigel,Sabine; Andreeva,Kalina; Rouchka,Eric; Clem,Brian F.

doi:10.3892/ol.2024.14755

Bioinformatics analysis of PSAT1 loss identifies downstream pathways regulated in EGFR mutant NSCLC and a selective gene signature for predicting the risk of relapse

Authors:
- Rumeysa Biyik‑Sit
- Sabine Waigel
- Kalina Andreeva
- Eric Rouchka
- Brian F. Clem
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Affiliations: Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY 40202, USA, Brown Cancer Center, Louisville, KY 40202, USA, Kentucky IDeA Network of Biomedical Research Excellence Bioinformatics Core, University of Louisville, Louisville, KY 40202, USA
Published online on: October 17, 2024 https://doi.org/10.3892/ol.2024.14755
Article Number: 9
Copyright: © Biyik‑Sit et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The majority of malignant tumors exhibit an altered metabolic phenotype that ultimately provides the required energy and molecular precursors necessary for unregulated cell division. Within this, phosphoserine aminotransferase 1 (PSAT1) is involved in de novo serine biosynthesis and its activity promotes various biochemical processes, including one‑carbon metabolism. It also directly generates α‑ketoglutarate (α‑KG), a Kreb cycle intermediate and epigenetic‑regulating metabolite. Prior studies examining PSAT1 depletion have identified individual affected downstream pathways, such as GSK3β and E2F, in several cancer types, including non‑small‑cell lung cancer (NSCLC). However, global gene expression examination in response to PSAT1 loss, particularly in EGFR mutant NSCLC, has not been unexplored. Transcriptional profiling of EGFR mutant NSCLC cells with or without stable knock‑down of PSAT1 identified differentially expressed genes (DEGs) enriched in several metabolic pathways required for cell division, including amino acid and nucleotide biosynthesis. Supplementation studies involving non‑essential amino acids, nucleosides and α‑KG partially restored defects in anchorage‑independent growth due to the knockdown of PSAT1. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analysis identified potential impacts on actin cytoskeleton arrangement and β‑catenin activity, which were rescued by PSAT1 re‑expression. Finally, a comparative analysis of PSAT1 DEGs against transcripts enriched in patient EGFR mutant lung tumors identified a gene signature that is associated with overall and relapse‑free survival (RFS) and was able to distinguish low or high‑risk populations for RFS in early‑stage EGFR mutant NSCLC. Overall, investigating genes altered by PSAT1 loss confirmed known PSAT1‑regulated cellular pathways, identified a previously unknown role in the mediation of cytoskeleton arrangement in EGFR mutant NSCLC cells and allowed for the characterization of a gene signature with putative predictive potential for RFS in early‑stage disease.

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