The
hydroxamic acid (HAA) analogue pan-
histone deacetylase (
HDAC) inhibitors (HDIs)
LAQ824 and
LBH589 have been shown to induce acetylation and inhibit the
ATP binding and chaperone function of
heat shock protein (HSP) 90. This promotes the polyubiquitylation and degradation of the pro-growth and pro-survival client
proteins Bcr-Abl, mutant FLT-3, c-Raf, and AKT in human
leukemia cells. HDAC6 is a member of the class IIB HDACs. It is predominantly cytosolic, microtubule-associated
alpha-tubulin deacetylase that is also known to promote aggresome inclusion of the misfolded polyubiquitylated
proteins. Here we demonstrate that in the Bcr-abl oncogene expressing human
leukemia K562 cells, HDAC6 can be co-immunoprecipitated with HSP90, and the knock-down of HDAC6 by its
siRNA induced the acetylation of HSP90 and
alpha-tubulin. Depletion of HDAC6 levels also inhibited the binding of HSP90 to
ATP, reduced the chaperone association of HSP90 with its client
proteins, e.g. Bcr-Abl, and induced polyubiquitylation and partial depletion of Bcr-Abl. Conversely, the ectopic overexpression of HDAC6 inhibited LAQ824-induced acetylation of HSP90 and
alpha-tubulin and reduced LAQ824-mediated depletion of Bcr-Abl, AKT, and c-Raf. Collectively, these findings indicate that HDAC6 is also an HSP90 deacetylase. Targeted inhibition of HDAC6 leads to acetylation of HSP90 and disruption of its chaperone function, resulting in polyubiquitylation and depletion of pro-growth and pro-survival HSP90 client
proteins including Bcr-Abl. Depletion of HDAC6 sensitized human
leukemia cells to HAA-HDIs and
proteasome inhibitors.