We applied a combined data mining and experimental validation Approach for the discovery of germ cell-specific genes aberrantly expressed in
cancer. Six of 21 genes with confirmed germ cell specificity were detected in
tumors, indicating that ectopic activation of testis-specific genes in
cancer is a frequent phenomenon. Most surprisingly one of the genes represented
lactate dehydrogenase C (LDHC), the germ cell-specific member of the
lactate dehydrogenase family. LDHC escapes from transcriptional repression, resulting in significant expression levels in virtually all
tumor types tested. Moreover, we discovered aberrant splicing of LDHC restricted to
cancer cells, resulting in four novel
tumor-specific variants displaying structural alterations of the catalytic domain. Expression of LDHC in
tumors is neither mediated by gene promotor demethylation, as previously described for other germ cell-specific genes activated in
cancer, nor induced by
hypoxia as demonstrated for
enzymes of the glycolytic pathway. LDHC represents the first
lactate dehydrogenase isoform with restriction to
tumor cells. In contrast to other LDH
isoenzymes, LDHC has a preference for
lactate as a substrate. Thus LDHC activation in
cancer may provide a metabolic rescue pathway in
tumor cells by exploiting
lactate for
ATP delivery.