Repression of GCN5 expression or activity attenuates c-MYC expression in non-small cell lung cancer.

Lung cancer causes the highest mortality in cancer-related deaths. As these cancers often become resistant to existing therapies, definition of novel molecular targets is needed. Epigenetic modifiers may provide such targets. Recent reports suggest that the histone acetyltransferase (HAT) module within the transcriptional coactivator SAGA complex plays a role in cancer, creating a new link between epigenetic regulators and this disease. GCN5 serves as a coactivator for MYC target genes, and here we investigate links between GCN5 and c-MYC in non-small cell lung cancer (NSCLC). Our data indicate that both GCN5 and c-MYC proteins are upregulated in mouse and human NSCLC cells compared to normal lung epithelial cells. This trend is observable only at the protein level, indicating that this upregulation occurs post-transcriptionally. Human NSCLC tissue data provided by The Cancer Genome Atlas (TCGA) indicates that and expression are positively associated with one another and with the expression of target genes. Depletion of GCN5 in NSCLC cells reduces c-MYC expression, cell proliferation, and increases the population of necrotic cells. Similarly, inhibition of the GCN5 catalytic site using a commercially available probe reduces c-MYC expression, cell proliferation, and increases the percentage of cells undergoing apoptosis. Our findings suggest that GCN5 might provide a novel target for inhibition of NSCLC growth and progression.