LDHAα, a lactate dehydrogenase A isoform, promotes glycolysis and tumor progression.

Abstract

Lactate dehydrogenase A (LDHA) is upregulated in multiple cancer types and contributes to the Warburg effect. Several studies have found that many tumor-related genes have subtypes and play important roles in promoting cancer development. Here, we identified a novel LDHA transcript, which produced a new protein 3 kDa larger than LDHA, which we named LDHAα. We found that multiple cancer cell lines express LDHAα, and ectopic expression of LDHAα led to a higher proliferation and migration rate in vitro. Ectopic expression of LDHAα could also promote tumor cell growth in vivo. Conversely, deletion of LDHAα by CRISPR-sgRNA significantly inhibited the growth of tumor cells. LDHAα was found to be mainly located in the cytoplasm, and overexpression or deletion of LDHAα could significantly affect the glucose uptake and lactate production of tumor cells. Further investigation showed that c-MYC and FOXM1 could markedly modulate the expression of both LDHA and LDHAα, especially c-MYC. We found that a small molecular compound targeting LDHA could also inhibit the enzyme activity of LDHAα. LDHAα, LDHA and c-MYC expression was significantly higher in human acute lymphocytic leukemia and colorectal cancer tissue specimens compared to normal controls. In conclusion, our study identified LDHAα as a subtype of LDHA and highlighted its critical role in tumor metabolism, providing a potential new therapeutic target for tumor diagnosis and treatment.