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Role of Acetylation and Extracellular Location of Heat Shock Protein 90 in Tumor Cell Invasion

¹ Medical College of Georgia Cancer Center, Augusta, Georgia; ² School of Pharmacy, East China University of Science and Technology, Shanghai, China; and ³ Novartis Institute for Biomedical Research, Inc., Cambridge, Massachusetts

Requests for reprints: Kapil Bhalla, 1120 15th Street, CN2101A, Augusta, GA 30912. Phone: 706-721-0463; Fax: 706-721-0469; E-mail: kbhalla{at}mcg.edu.

Key Words: hsp90 • LBH589 • MMP-2

Heat shock protein (hsp) 90 is an ATP-dependent molecular chaperone that maintains the active conformation of client oncoproteins in cancer cells. An isoform, hsp90, 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 hsp90 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 hsp90, acetylation of all seven lysines increased the binding of hsp90 to 17-allyl-amino-demethoxy geldanamycin. Notably, after treatment with the pan-HDAC inhibitor panobinostat (LBH589), the extracellular hsp90 was hyperacetylated and it bound to MMP-2, which was associated with increased in vitro tumor cell invasiveness. Treatment with antiacetylated hsp90 antibody inhibited in vitro invasion by tumor cells. Thus, reversible hyperacetylation modulates the intracellular and extracellular chaperone function of hsp90, and targeting extracellular hyperacetylated hsp90 may undermine tumor invasion and metastasis. [Cancer Res 2008;68(12):4833–42]