Tumors of nearly every origin activate the expression of genes which is otherwise restricted to gametogenic cells. These genes encode proteins termed cancer/testis (CT) antigens, since expression outside of their naturally immune-privileged site can evoke an immune response. Despite extensive efforts to exploit CT antigens as immunotherapeutic targets, investigation of whether these proteins participate in tumorigenic processes has lagged. Here, we discuss emerging evidence that demonstrates that CT antigens can confer a selective advantage to tumor cells by promoting oncogenic processes or permitting evasion of tumor-suppressive mechanisms. These advances indicate the inherent flexibility of tumor cell regulatory networks to engage aberrantly expressed proteins to promote neoplastic behaviors, which could ultimately present novel therapeutic entry points.

Cancer testis antigens (CTAs) are proteins whose expression is normally restricted to the testis but anomalously activated in human cancer. In sperm, a number of CTAs support energy generation, however whether they contribute to tumor metabolism is not understood. We describe human COX6B2, a component of cytochrome c oxidase (complex IV). COX6B2 is expressed in human lung adenocarcinoma (LUAD) and expression correlates with reduced survival time. COX6B2, but not its somatic isoform COX6B1, enhances activity of complex IV, increasing oxidative phosphorylation (OXPHOS) and NAD+ generation. Consequently, COX6B2-expressing cancer cells display a proliferative advantage, particularly in low oxygen. Conversely, depletion of COX6B2 attenuates OXPHOS and collapses mitochondrial membrane potential leading to cell death or senescence. COX6B2 is both necessary and sufficient for growth of human tumor xenografts in mice. Our findings reveal a previously unappreciated, tumor specific metabolic pathway hijacked from one of the most ATP-intensive processes in the animal kingdom: sperm motility.

Ewing sarcoma is characterized by a pathognomonic chromosomal translocation that generates the EWSR1-FLI1 chimeric transcription factor. The transcriptional targets of EWSR1-FLI1 that are essential for tumorigenicity are incompletely defined. Here, we found that EWSR1-FLI1 modulates the expression of cancer/testis (CT) antigen genes, whose expression is biased to the testes but is also activated in cancer. Among these CT antigens, fetal and adult testis expressed 1 (FATE1) is most robustly induced. EWSR1-FLI1 associates with the GGAA repeats in the proximal promoter of FATE1, which exhibits accessible chromatin exclusively in mesenchymal progenitor cells (MPCs) and Ewing sarcoma cells. Expression of EWSR1-FLI1 in non-Ewing sarcoma cells and in MPCs enhances FATE1 mRNA and protein expression. Conversely, depletion of EWSR1-FLI1 in Ewing sarcoma cells leads to a loss of FATE1 expression. Importantly, we found that FATE1 is required for survival and anchorage-independent growth in Ewing sarcoma cells via attenuating the accumulation of BNIP3L, a BH3-only protein that is toxic when stabilized. This action appears to be mediated by the E3 ligase RNF183. We propose that engaging FATE1 function can permit the bypass of cell death mechanisms that would otherwise inhibit tumor progression.

Cancer/testis (CT) antigens are proteins whose expression is normally restricted to germ cells yet aberrantly activated in tumors, where their functions remain relatively cryptic. Here we report that ZNF165, a CT antigen frequently expressed in triple-negative breast cancer (TNBC), associates with SMAD3 to modulate transcription of transforming growth factor β (TGFβ)-dependent genes and thereby promote growth and survival of human TNBC cells. In addition, we identify the KRAB zinc finger protein, ZNF446, and its associated tripartite motif protein, TRIM27, as obligate components of the ZNF165-SMAD3 complex that also support tumor cell viability. Importantly, we find that TRIM27 alone is necessary for ZNF165 transcriptional activity and is required for TNBC tumor growth in vivo using an orthotopic xenograft model in immunocompromised mice. Our findings indicate that aberrant expression of a testis-specific transcription factor is sufficient to co-opt somatic transcriptional machinery to drive a pro-tumorigenic gene expression program in TNBC.

Cluster BG of the actinobacteriophage was formed upon discovery of five novel bacteriophages isolated by enrichment from their host, Streptomyces griseus subsp. griseus strain ATCC 10137. Four members of this cluster (BabyGotBac, Maih, TP1605, and YDN12) share over 89% average nucleotide identity, while the other (Xkcd426) has only 72% similarity to other cluster members.