Abstract
The integrated stress response (ISR) has been associated with malignancy in cancer cells, with evidence for the eIF2α kinases PERK and GCN2 having important roles in tumor survival. For GCN2, this association has been described in the literature with an emphasis on its role as an eIF2α kinase, and in the activation of ATF4. However, recent findings have shown deviations from this main view. First, the lack of GCN2 can be compensated for by other eIF2α kinases in a cancer model. Second, several functions of GCN2 have been described that are independent of the ISR. These findings suggest that, although GCN2 indeed appears to be important in cancer development and progression, its involvement in the ISR is not the only and possibly not the main factor. The aim of this project was therefore, to identify functions of GCN2, which are relevant for development and progression of cancer. We analyzed gene expression data from a biobank of cervical cancer patient samples to obtain correlations between GCN2 and other genes in the samples. Then used a gene set enrichment analysis (GSEA) to compare the sets of genes correlated to GCN2 to a database of gene signatures. The analysis revealed the presence of several cancer-relevant functions reflected in our data. Some of these functions were consistent with sporadic reports of the involvement of GCN2 in processes other than the ISR, such as the Warburg effect. Genes related to mitosis and the centrosome were selected for further inspection because of the importance of these genes in chromosome missegregation, an important hallmark of cancer. The expression of these candidate genes was found increased in a cell line overexpressing GCN2, which indicates that the increase is a direct consequence of high GCN2 levels. With this study, candidates for novel functions of GCN2 are presented, which open new avenues for future research.