Lysine acetylation activates 6-phosphogluconate dehydrogenase to promote tumor growth

Mol Cell. 2014 Aug 21;55(4):552-65. doi: 10.1016/j.molcel.2014.06.020. Epub 2014 Jul 17.


Although the oxidative pentose phosphate pathway is important for tumor growth, how 6-phosphogluconate dehydrogenase (6PGD) in this pathway is upregulated in human cancers is unknown. We found that 6PGD is commonly activated in EGF-stimulated cells and human cancer cells by lysine acetylation. Acetylation at K76 and K294 of 6PGD promotes NADP(+) binding to 6PGD and formation of active 6PGD dimers, respectively. Moreover, we identified DLAT and ACAT2 as upstream acetyltransferases of K76 and K294, respectively, and HDAC4 as the deacetylase of both sites. Expressing acetyl-deficient mutants of 6PGD in cancer cells significantly attenuated cell proliferation and tumor growth. This is due in part to reduced levels of 6PGD products ribulose-5-phosphate and NADPH, which led to reduced RNA and lipid biosynthesis as well as elevated ROS. Furthermore, 6PGD activity is upregulated with increased lysine acetylation in primary leukemia cells from human patients, providing mechanistic insights into 6PGD upregulation in cancer cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyl-CoA C-Acetyltransferase / metabolism*
  • Acetylation
  • Animals
  • Cell Line, Tumor
  • Dihydrolipoyllysine-Residue Acetyltransferase / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Histone Deacetylases / metabolism*
  • Humans
  • Leukemia / metabolism
  • Leukemia / pathology*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Lysine / metabolism*
  • Mice
  • NADP / metabolism
  • Neoplasms, Experimental
  • Phosphogluconate Dehydrogenase / metabolism*
  • Protein Binding / physiology
  • Protein Multimerization


  • NADP
  • Phosphogluconate Dehydrogenase
  • Dihydrolipoyllysine-Residue Acetyltransferase
  • Acetyl-CoA C-Acetyltransferase
  • Histone Deacetylases
  • Lysine