Role of acetylation and extracellular location of heat shock protein 90alpha in tumor cell invasion.
Heat shock protein (hsp) 90 is an ATP-dependent molecular chaperone that maintains the active conformation of client oncoproteins in cancer cells. An isoform, hsp90alpha, promotes extracellular maturation of matrix metalloproteinase (MMP)-2, involved in tumor invasion and metastasis. Knockdown of histone deacetylase (HDAC) 6, which deacetylates lysine residues in hsp90, induces reversible hyperacetylation and attenuates ATP binding and chaperone function of hsp90. Here, using mass spectrometry, we identified seven lysine residues in hsp90alpha that are hyperacetylated after treatment of eukaryotic cells with a pan-HDAC inhibitor that also inhibits HDAC6. Depending on the specific lysine residue in the middle domain involved, although acetylation affects ATP, cochaperone, and client protein binding to hsp90alpha, acetylation of all seven lysines increased the binding of hsp90alpha to 17-allyl-amino-demethoxy geldanamycin. Notably, after treatment with the pan-HDAC inhibitor panobinostat (LBH589), the extracellular hsp90alpha was hyperacetylated and it bound to MMP-2, which was associated with increased in vitro tumor cell invasiveness. Treatment with antiacetylated hsp90alpha antibody inhibited in vitro invasion by tumor cells. Thus, reversible hyperacetylation modulates the intracellular and extracellular chaperone function of hsp90, and targeting extracellular hyperacetylated hsp90alpha may undermine tumor invasion and metastasis.
Pubmed ID: 18559531 RIS Download
Acetylation | Adenosine Triphosphate | Benzoquinones | Breast Neoplasms | Cells, Cultured | Collagen | Drug Combinations | HSP90 Heat-Shock Proteins | Histone Deacetylase Inhibitors | Histone Deacetylases | Humans | Hydroxamic Acids | Immunoblotting | Immunoprecipitation | Indoles | Lactams, Macrocyclic | Laminin | Lysine | Matrix Metalloproteinase 2 | Mutagenesis, Site-Directed | Neoplasm Invasiveness | Protein Processing, Post-Translational | Proteoglycans | Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization | p300-CBP Transcription Factors