Multiple splice variants of lactate dehydrogenase C selectively expressed in human cancer.
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.
Koslowski
Michael
M
Department of Internal Medicine, University Mainz, 55131 Mainz, Germany.
Türeci
Ozlem
O
Bell
Carolin
C
Krause
Patricia
P
Lehr
Hans-Anton
HA
Brunner
Joachim
J
Seitz
Gerhard
G
Nestle
Frank Oliver
FO
Huber
Christoph
C
Sahin
Ugur
U
D017398:Alternative Splicing; D030561:Databases, Nucleic Acid; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics*; D007770:L-Lactate Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics*; D008297:Male; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013736:Testicular Neoplasms / Q000201:enzymology / Q000235:genetics; D014158:Transcription, Genetic
D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase; C409673:lactate dehydrogenase C4