LDH-A Acetylation: Implication in Cancer

Upregulation of lactate dehydrogenase A (LDH-A) is commonly observed in many tumor types. Previous studies have revealed LDH-A transcriptional activation by the increased activity of Myc and HIF in human cancers. Is LDH-A regulated by post-translational modifications during tumorigenesis? If so, can such knowledge be used to assist cancer early diagnosis and treatment? Reprogramming of energy metabolism, particularly the elevated glucose uptake, glycolysis and lactate production, is a hallmark of cancer. In order to support rapid cancer cell growth, glycolysis is highly elevated to provide metabolic intermediates for macromolecule biosynthesis. Instead of entering mitochondria to fuel the tricarbolic acid (TCA) cycle and oxidative phosphorylation for efficient energy production, a large fraction of pyruvate in cancer cells is converted into lactate by LDH, accompanied by NAD+ regeneration to maintain high glycolysis rate (Figure1). Moreover, the excess lactate transported out of cytoplasm may condition the microenvironment, which promotes interaction between cancer cells and stromal cells, eventually resulting in increased cancer cell migration and invasion. LDH is a homoor hetero-tetrameric enzyme consisting of two different subunits encoded by the highly related genes, LDH-A and LDH-B. Both LDH-A and -B catalyze the reversible conversion between pyruvate and lactate using NAD+ as a cofactor. However, LDH-A favors the conversion of pyruvate into lactate, while LDH-B prefers the inverse reaction. Actually, it has long been known that many tumor cells express high levels of LDH-A, including non-small-cell lung cancer, colorectal cancer, and breast cancer. In many tumors, elevated LDH-A levels have been correlated with poor prognosis and resistance to chemotherapy and radiotherapy. It has been reported that inhibition of LDH-A by either RNA interference or pharmacological agents blocks tumor progression in vivo, supporting an important role of elevated LDH-A in tumorigenesis and LDH-A as a potential therapeutic target. Due to the critical function of LDH-A in tumor