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 GCN5 and c-MYC expression are positively associated with one another and with the expression of c-MYC 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.

Deficient LRRC8A-dependent volume-regulated anion channel activity is associated with male infertility in mice.

Ion channel-controlled cell volume regulation is of fundamental significance to the physiological function of sperm. In addition to volume regulation, LRRC8A-dependent volume-regulated anion channel (VRAC) activity is involved in cell cycle progression, insulin signaling, and cisplatin resistance. Nevertheless, the contribution of LRRC8A and its dependent VRAC activity in the germ cell lineage remain unknown. By utilizing a spontaneous Lrrc8a mouse mutation (c.1325delTG, p.F443*) and genetically engineered mouse models, we demonstrate that LRRC8A-dependent VRAC activity is essential for male germ cell development and fertility. Lrrc8a-null male germ cells undergo progressive degeneration independent of the apoptotic pathway during postnatal testicular development. Lrrc8a-deficient mouse sperm exhibit multiple morphological abnormalities of the flagella (MMAF), a feature commonly observed in the sperm of infertile human patients. Importantly, we identified a human patient with a rare LRRC8A hypomorphic mutation (c.1634G>A, p.Arg545His) possibly linked to Sertoli cell-only syndrome (SCOS), a male sterility disorder characterized by the loss of germ cells. Thus, LRRC8A is a critical factor required for germ cell development and volume regulation in the mouse, and it might serve as a novel diagnostic and therapeutic target for SCOS patients.