Lysine-5 Acetylation Negatively Regulates Lactate Dehydrogenase A and Is Decreased in Pancreatic Cancer

Menée in vitro, à l'aide de xénogreffes et sur 127 échantillons tumoraux prélevés sur des patients chinois atteints d'un cancer du pancréas, cette étude met en évidence un mécanisme par lequel une acétylation de la lysine 5 régule l'expression de la lactate déshydrogénase A dans les tumeurs

Résumé en anglais

Tumor cells commonly have increased glucose uptake and lactate accumulation. Lactate is produced from pyruvate by lactate dehydrogenase A (LDH-A), which is frequently overexpressed in tumor cells and is important for cell growth. Elevated transcription by c-Myc or HIF1± may contribute to increased LDH-A in some cancer types. Here, we show that LDH-A is acetylated at lysine 5 (K5) and that this acetylation inhibits LDH-A activity. Furthermore, the K5-acetylated LDH-A is recognized by the HSC70 chaperone and delivered to lysosomes for degradation. Replacement of endogenous LDH-A with an acetylation mimetic mutant decreases cell proliferation and migration. Importantly, K5 acetylation of LDH-A is reduced in human pancreatic cancers. Our study reveals a mechanism of LDH-A upregulation in pancreatic cancers.

º Acetylation inhibits LDH-A activity
º Acetylation targets LDH-A for chaperone-mediated autophagy
º SIRT2 regulates LDH-A acetylation
º Pancreatic cancer has decreased acetylation and increased protein levels of LDH-A