Sperm-specific COX6B2 Enhances Oxidative Phosphorylation, Proliferation, and Survival in Lung Adenocarcinoma

Cancer Testes Antigens (CTAs) are genes whose expression is normally restricted to the testes but anomalously activated in cancer. A number of CTAs are implicated in supporting the unique energy-demands of sperm, however if and how these proteins contribute to metabolic pathways in tumors has not been investigated. Here we describe the mechanism of one such cryptic protein, COX6B2, a sperm-specific component of cytochrome c oxidase (CcO). COX6B2 is frequently expressed in human lung adenocarcinoma (LUAD), where it correlates with reduced patient survival. In tumor cells, COX6B2, but not its somatic isoform COX6B1, enhances activity of CcO, increasing ATP and NAD+ generation. Consequently, COX6B2-expressing tumor cells display a proliferative advantage, particularly in low oxygen conditions. Conversely, depletion of COX6B2 attenuates ATP production, and causes a collapse in mitochondrial membrane potential leading to programmed cell death or senescence. Importantly, we find that COX6B2 is both necessary and sufficient for growth of tumors in vivo. Our findings reveal a previously unappreciated, tumor specific metabolic pathway that is hijacked from one of the most ATP-intensive processes in the animal kingdom: sperm motility.