title: FK228 inhibits Hsp90 chaperone function in K562 cells via hyperacetylation of Hsp70.
abstract: Some pan-histone-deacetylase (HDAC) inhibitors have recently been reported to exert their anti-leukemia effect by inhibiting the activity of class IIB HDAC6, which is the deacetylase of Hsp90 and alpha-tubulin, thereby leading to hyperacetylation of Hsp90, disruption of its chaperone function and apoptosis. In this study, we compared the effect of a class I HDAC inhibitor FK228 with the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) on the Hsp90 chaperone function of K562 cells. We demonstrated that, although having a weaker inhibitory effect on HDAC6, FK228 mediated a similar disruption of Hsp90 chaperone function compared to SAHA. Unlike SAHA, FK228 did not mediate hyperacetylation of Hsp90, instead the acetylation of Hsp70 was increased and Bcr-Abl was increasingly associated with Hsp70 rather than Hsp90, forming an unstable complex that promotes Bcr-Abl degradation. These results indicated that FK228 may disrupt the function of Hsp90 indirectly through acetylation of Hsp70 and inhibition of its function.
authors.affiliation: Department of Pathology, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Sheng-Yu
authors.initials: SY
authors.lastname: Wang
authors.forename: Xu-Hui
authors.initials: XH
authors.lastname: Zhang
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Chun-Mei
authors.initials: CM
authors.lastname: Hou
authors.forename: Yuan-Ji
authors.initials: YJ
authors.lastname: Xu
authors.forename: Zhi-Yan
authors.initials: ZY
authors.lastname: Du
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Yu
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D047630:Depsipeptides / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D018832:Molecular Chaperones / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; C087123:romidepsin