Our understanding of non-histone acetylation as a means of cellular regulation is in its infancy. Using a mass spectrometry approach we identified acetylated lysine residues and monitored acetylation changes across the proteome as a consequence of metabolic stress (hypoxia). We observed changes in acetylation status of non-histone lysines in tumor cells. Through the use of small molecule inhibitors of histone deacetylase enzymes (HDACs) and siRNA screening identified HDAC6 as a pro-survival regulator of lysine acetylation during hypoxia. The phospho-binding protein 14-3-3ζ acts as a signaling hub controlling a network of interacting partners and oncogenic pathways. We show here that lysines within the 14-3-3ζ binding pocket and protein-protein interface can be modified by acetylation. The positive charge on two of these lysines, K49 and K120, is critical for coordinating 14-3-3ζ-phosphoprotein interactions. Through screening, we identified HDAC6 as the K49/K120 deacetylase. Inhibition of HDAC6 blocks 14-3-3ζ interactions with two well-described interacting partners, Bad and AS160, which triggers their dephosphorylation at S112 and T642, respectively. Expression of an acetylation-refractory K49R/K120R mutant of 14-3-3ζ rescues both the HDAC6 inhibitor-induced loss of interaction and S112/T642 phosphorylation. Furthermore, expression of the K49R/K120R mutant of 14-3-3ζ inhibits the cytotoxicity of HDAC6 inhibition. These data demonstrate a novel role for HDAC6 in controlling 14-3-3ζ binding activity.
College and Department
Physical and Mathematical Sciences; Chemistry and Biochemistry
BYU ScholarsArchive Citation
Mortenson, Jeffrey Benjamin, "Histone Deacetylase 6 (HDAC6) Is Critical for Tumor Cell Survival and Promotes the Pro-Survival Activity of 14-3-3ζ viaDeacetylation of Lysines Within the14-3-3ζ Binding Pocket" (2015). All Theses and Dissertations. 5568.
Non-histone acetylation, cell survival, 14-3-3, HDAC6