title: Lysine-5 acetylation negatively regulates lactate dehydrogenase A and is decreased in pancreatic cancer.
abstract: 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 HIF1α 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.
authors.affiliation: Ministry of Education Key Laboratory of Molecular Medicine, Shanghai Medical College and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Di
authors.initials: D
authors.lastname: Zhao
authors.forename: Shao-Wu
authors.initials: SW
authors.lastname: Zou
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.forename: Yan
authors.initials: Y
authors.lastname: Mo
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Yan-Hui
authors.initials: YH
authors.lastname: Xu
authors.forename: Bo
authors.initials: B
authors.lastname: Dong
authors.forename: Yue
authors.initials: Y
authors.lastname: Xiong
authors.forename: Qun-Ying
authors.initials: QY
authors.lastname: Lei
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
mesh_terms: D000107:Acetylation; D000818:Animals; D001343:Autophagy / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000080864:Lactate Dehydrogenase 5; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D056565:Sirtuin 2 / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014183:Transplantation, Heterologous
chemical_list: D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; C474199:SIRT2 protein, human; D056565:Sirtuin 2; D008239:Lysine