Inhibition of Histone Deacetylase 6 Acetylates and Disrupts the Chaperone Function of Heat Shock Protein 90

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 α-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 α-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 α-tubulin and reduced depletion of Bcr-Abl, and that HDAC6 is also HSP90 of HDAC6 to acetylation of HSP90 and of its chaperone in polyubiquitylation and depletion of pro-growth and pro-survival HSP90 client proteins Bcr-Abl. Depletion of HDAC6 human leukemia to and 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 α-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 α-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 α-tubulin and reduced depletion of Bcr-Abl, and that HDAC6 is also HSP90 of HDAC6 to acetylation of HSP90 and of its chaperone in polyubiquitylation and depletion of pro-growth and pro-survival HSP90 client proteins Bcr-Abl. Depletion of HDAC6 human leukemia to and have that heat shock protein (HSP) heat shock hydroxamic α-tubulin heat shock hydroxamic α-tubulin the chaperone protein the and of a of protein e.g. the mutant Bcr-Abl, mutant FLT-3, and c-Raf, in and is by HSP90 ATP binding and binding to the HSP90 in the of HSP90 with a that the client proteins with of that the misfolded client proteins to a with and degradation by the and its analogue to the binding the and the chaperone function of HSP90 ATP binding to HSP90, with HSP90 the that the misfolded client proteins and to polyubiquitylation and degradation and that the acetylation and of the of the by to the of the the of and the acetylation of and binding the also the acetylation of of a of binding and of have been and and with the hydroxamic acid analogue (HAA) inhibitors (HDIs) LAQ824 and LBH589 been shown to induce acetylation of of and also been to induce acetylation of HSP90 This is with and depletion of Bcr-Abl, and in mutant in the to of the is HSP90, that its by acetylation and the chaperone function of HDAC6 is predominantly a microtubule-associated member of the class IIB of HDAC6 is in and a that polyubiquitylated misfolded proteins and the The of HDAC6 α-tubulin deacetylase is inhibited by the HDAC6 also been to the polyubiquitylated misfolded proteins the of the misfolded protein of HDAC6 that HDAC6 be in HSP90 the we HDAC6 the acetylation of HSP90 and depletion of HDAC6 the chaperone function of HSP90 in human leukemia and of of LBH589 and LAQ824 by and and α-tubulin and and and and HDAC6 K562 leukemia and leukemia a in of and in in The a to the and of the and of the to of the of Bcr-Abl, and proteins and and by the of The of a of HSP90 and to in and and proteins the protein HSP90 of protein HSP90 and with and HSP90 of protein The of HSP90 in the by a of of with The of by the that in a and of of HSP90 and the in and the and by with HSP90 protein and The in the and proteins with the to with HSP90, of and the with and The with and of proteins the and and by of of HDAC6 by of and of the This and the K562 by a and of HDAC6 siRNA with the with HDAC6 siRNA This a to the in the HDAC6 a siRNA HDAC6 by The knock-down with reduced of HDAC6 of of the of LAQ824 and LBH589 HSP90 acetylation in human leukemia and cells. of to LAQ824 of HSP90 by with that of HSP90 in a the levels of HSP90 to LBH589 a HSP90 acetylation with known to inhibit the of class induce HSP90 acetylation to the α-tubulin deacetylase of a in HSP90 of K562 with LAQ824 LBH589 HSP90 the with and the levels of HSP90 by and acetylation of HSP90 with binding of to HSP90 the analogue of the ATP binding of HSP90, also in the binding of to HSP90, with we the of the function of HSP90 a chaperone of K562 to LAQ824 the and the binding of to HSP90 to been with with LAQ824 the chaperone association of HSP90 to in the chaperone association also with LBH589 have shown that the in the chaperone association of the client proteins to the polyubiquitylation and of the client proteins in the the client proteins degradation by the with with LAQ824 in the by with the of K562 with LAQ824 the polyubiquitylation of proteins in the with polyubiquitylation of proteins also with with LAQ824 and with with LAQ824 the levels of in K562 also LAQ824 and AKT levels the levels of the α-tubulin and in a the chaperone association of HSP90 to in polyubiquitylation and degradation of Bcr-Abl. K562 with the of LAQ824 of the with K562 with the of LAQ824 of the with of K562 with LAQ824 the and with The levels of the K562 with the of LAQ824 the with c-Raf, The levels of the of the acetylation of α-tubulin and HSP90 by LAQ824 the that of HDAC6 be acetylation and of the chaperone function of we HDAC6 is co-immunoprecipitated with shown in in K562 HDAC6 be co-immunoprecipitated with with LAQ824 LBH589 with reduced the of HDAC6 that be co-immunoprecipitated with HSP90, by LAQ824 with a in the levels of the levels of to the of the ectopic overexpression of HDAC6 LAQ824-induced acetylation of α-tubulin and HSP90 and of in K562 cells. of HDAC6 in K562 cells, and the of and the overexpression of HDAC6 in with the K562 cells, a in HDAC6 in cells. The and a overexpression of HDAC6 be the its in the of in the levels in with the in the levels of α-tubulin of in LAQ824 HDAC6 in and cells. ectopic overexpression of HDAC6 also inhibited LAQ824-induced HSP90 acetylation in with the of LAQ824 in cells, a of and levels in to HSP90, and ectopic overexpression of HDAC6 acetylation of α-tubulin and K562 with the of LAQ824 LBH589 with and to HSP90 the with K562 with HDAC6 the the with LAQ824 the with The levels of the and with LAQ824 of HSP90 with and with LAQ824 the with The levels of the demonstrate that HDAC6 a deacetylase α-tubulin also HSP90, we a siRNA to HDAC6 K562 to inhibit the of shown in with the in the HDAC6 levels by the siRNA to HDAC6 induced the acetylation of α-tubulin in K562 This to the of with HSP90 by with LAQ824 also levels with also induced the acetylation of HSP90, the levels of HSP90 HDAC6 is a deacetylase α-tubulin also HSP90 acetylation induced by HDAC6 the binding of ATP to HSP90, also with LAQ824 This that HSP90 acetylation in the chaperone function of HSP90, a also by the of of association of heat shock with HSP90 in to with acetylation and of HSP90 function of the chaperone association of with HSP90 shown in with polyubiquitylation of and depletion of the levels of Bcr-Abl, c-Raf, and the The of depletion of the client proteins is of in the levels of and of polyubiquitylation by the the client the of degradation of the client proteins by the a that in HDAC6 to the of misfolded proteins we the of polyubiquitylated and misfolded proteins induced by of the K562 and with LAQ824 that with LAQ824 induced in cells. This that the of the by aggresome to the of LAQ824 with of HSP90 and the to with LAQ824 and the of misfolded and polyubiquitylated proteins in the also in K562 of HDAC6 acetylation and the chaperone function of K562 with the the that the siRNA to HDAC6 a the K562 expressing HDAC6 siRNA K562 with The levels of the to HSP90, with the with and with K562 expressing HDAC6 siRNA K562 with and the with K562 expressing HDAC6 siRNA K562 with the and the with the with The levels of the K562 expressing HDAC6 siRNA K562 with a of and LAQ824 the of by the The been that with the LAQ824 and LBH589 the chaperone function of HSP90, polyubiquitylation and degradation of the pro-growth and pro-survival Bcr-Abl, c-Raf, and AKT proteins in human leukemia Here we have the that HDAC6 is the deacetylase HSP90, and depletion of HDAC6 levels and is to be and acetylation and of HSP90 a chaperone The of HDAC6 in HSP90 with and inhibit induce the acetylation of ATP binding of It also is a of the of HDAC6 and is to inhibit the of induced the acetylation of LAQ824 and LBH589 inhibitors that inhibit the class and also class IIB by the acetylation of a the predominantly HDAC6 to the class IIB This the of HDAC6 a deacetylase the ectopic overexpression of HDAC6 acetylation of α-tubulin also of It is that HDAC6 overexpression inhibit be to of by The also that HDAC6 is co-immunoprecipitated with HSP90 and that association is inhibited with LAQ824 LBH589 This the of the HDAC6 in binding and The also shown to be binding of HDAC6 to the and misfolded proteins. It also shown to be the aggresome the that the knock-down of HDAC6 acetylation of HSP90 the of HDAC6 HSP90 also demonstrate knock-down of HDAC6 of its by acetylation of HSP90 the of acetylation of HSP90 reduced the binding of HSP90 to ATP, to be a with reduced the chaperone association of HSP90 with its client proteins Bcr-Abl, its polyubiquitylation and in the This by with acetylation of HSP90 induced by HDAC6 depletion the levels of client proteins, e.g. Bcr-Abl. that a of HDAC6 to the depletion of pro-growth and pro-survival HSP90 client proteins the of the chaperone function of client protein is to a be the of the the the client proteins, the and of the client It be that the and acetylation of HSP90 the association of HSP90 with its is known to be by HSP90 is in the It also be to the HSP90 that in the in acetylation of that the ectopic overexpression and of HDAC6 with the acetylation of with that α-tubulin is a the of the of HDAC6 HDAC6 also been shown to with been shown to acetylation of α-tubulin with microtubule-associated proteins, and of HDAC6 of its the and of It that the of and induced the levels of misfolded and polyubiquitylated proteins and expressing leukemia the of with also been shown to in the we have to HDAC6 by depletion of HDAC6 levels by also the of This in of aggresome by in of misfolded proteins, aggresome and to the induced by misfolded proteins the that aggresome is of a to misfolded proteins and that HDAC6 a in the of the misfolded is that in with the of HDAC6 is with and that inhibit HDAC6 to the of misfolded proteins by HSP90 inhibitors to be It be to the of a protein is of the and in and have that heat shock protein (HSP) heat shock hydroxamic α-tubulin heat shock hydroxamic α-tubulin the chaperone protein the and of a of protein e.g. the mutant Bcr-Abl, mutant FLT-3, and c-Raf, in and is by HSP90 ATP binding and binding to the HSP90 in the of HSP90 with a that the client proteins with of that the misfolded client proteins to a with and degradation by the and its analogue to the binding the and the chaperone function of HSP90 ATP binding to HSP90, with HSP90 the that the misfolded client proteins and to polyubiquitylation and degradation and that the acetylation and of the of the by to the of the the of and the acetylation of and binding the also the acetylation of of a of binding and of have been and and with the hydroxamic acid analogue (HAA) inhibitors (HDIs) LAQ824 and LBH589 been shown to induce acetylation of of and also been to induce acetylation of HSP90 This is with and depletion of Bcr-Abl, and in mutant in the to of the is HSP90, that its by acetylation and the chaperone function of HDAC6 is predominantly a microtubule-associated member of the class IIB of HDAC6 is in and a that polyubiquitylated misfolded proteins and the The of HDAC6 α-tubulin deacetylase is inhibited by the HDAC6 also been to the polyubiquitylated misfolded proteins the of the misfolded protein of HDAC6 that HDAC6 be in HSP90 the we HDAC6 the acetylation of HSP90 and depletion of HDAC6 the chaperone function of HSP90 in human leukemia cells. and of of LBH589 and LAQ824 by and and α-tubulin and and and and HDAC6 K562 leukemia and leukemia a in of and in in The a to the and of the and of the to of the of Bcr-Abl, and proteins and and by the of The of a of HSP90 and to in and and proteins the protein HSP90 of protein HSP90 and with and HSP90 of protein The of HSP90 in the by a of of with The of by the that in a and of of HSP90 and the in and the and by with HSP90 protein and The in the and proteins with the to with HSP90, of and the with and The with and of proteins the and and by of of HDAC6 by of and of the This and the K562 by a and of HDAC6 siRNA with the with HDAC6 siRNA This a to the in the HDAC6 a siRNA HDAC6 by The knock-down with reduced of HDAC6 of of and of of LBH589 and LAQ824 by and and α-tubulin and and and and HDAC6 K562 leukemia and leukemia a in of and in in The a to the and of the and of the to of the of Bcr-Abl, and proteins and and by the of The of a of HSP90 and to in and and proteins the protein HSP90 of protein HSP90 and with and HSP90 of protein The of HSP90 in the by a of of with The of by the that in a and of of HSP90 and the in and the and by with HSP90 protein and The in the and proteins with the to with HSP90, of and the with and The with and of proteins the and and by of of HDAC6 by of and of the This and the K562 by a and of HDAC6 siRNA with the with HDAC6 siRNA This a to the in the HDAC6 a siRNA HDAC6 by The knock-down with reduced of HDAC6 of of the of LAQ824 and LBH589 HSP90 acetylation in human leukemia and cells. of to LAQ824 of HSP90 by with that of HSP90 in a the levels of HSP90 to LBH589 a HSP90 acetylation with known to inhibit the of class induce HSP90 acetylation to the α-tubulin deacetylase of a in HSP90 of K562 with LAQ824 LBH589 HSP90 the with and the levels of HSP90 by and acetylation of HSP90 with binding of to HSP90 the analogue of the ATP binding of HSP90, also in the binding of to HSP90, with we the of the function of HSP90 a chaperone of K562 to LAQ824 the and the binding of to HSP90 to been with with LAQ824 the chaperone association of HSP90 to in the chaperone association also with LBH589 have shown that the in the chaperone association of the client proteins to the polyubiquitylation and of the client proteins in the the client proteins degradation by the with with LAQ824 in the by with the of K562 with LAQ824 the polyubiquitylation of proteins in the with polyubiquitylation of proteins also with with LAQ824 and with with LAQ824 the levels of in K562 also LAQ824 and AKT levels the levels of the α-tubulin and in a of the acetylation of α-tubulin and HSP90 by LAQ824 the that of HDAC6 be acetylation and of the chaperone function of we HDAC6 is co-immunoprecipitated with shown in in K562 HDAC6 be co-immunoprecipitated with with LAQ824 LBH589 with reduced the of HDAC6 that be co-immunoprecipitated with HSP90, by LAQ824 with a in the levels of the levels of to the of the ectopic overexpression of HDAC6 LAQ824-induced acetylation of α-tubulin and HSP90 and of in K562 cells. of HDAC6 in K562 cells, and the of and the overexpression of HDAC6 in with the K562 cells, a in HDAC6 in cells. The and a overexpression of HDAC6 be the its in the of in the levels in with the in the levels of α-tubulin of in LAQ824 HDAC6 in and cells. ectopic overexpression of HDAC6 also inhibited LAQ824-induced HSP90 acetylation in with the of LAQ824 in cells, a of and levels in to HSP90, and ectopic overexpression of HDAC6 acetylation of α-tubulin and K562 with the of LAQ824 LBH589 with and to HSP90 the with K562 with HDAC6 the the with LAQ824 the with The levels of the and with LAQ824 of HSP90 with and with LAQ824 the with The levels of the demonstrate that HDAC6 a deacetylase α-tubulin also HSP90, we a siRNA to HDAC6 K562 to inhibit the of shown in with the in the HDAC6 levels by the siRNA to HDAC6 induced the acetylation of α-tubulin in K562 This to the of with HSP90 by with LAQ824 also levels with also induced the acetylation of HSP90, the levels of HSP90 HDAC6 is a deacetylase α-tubulin also HSP90 acetylation induced by HDAC6 the binding of ATP to HSP90, also with LAQ824 This that HSP90 acetylation in the chaperone function of HSP90, a also by the of of association of heat shock with HSP90 in to with acetylation and of HSP90 function of the chaperone association of with HSP90 shown in with polyubiquitylation of and depletion of the levels of Bcr-Abl, c-Raf, and the The of depletion of the client proteins is of in the levels of and of polyubiquitylation by the the client the of degradation of the client proteins by the a that in HDAC6 to the of misfolded proteins we the of polyubiquitylated and misfolded proteins induced by of the K562 and with LAQ824 that with LAQ824 induced in cells. This that the of the by aggresome to the of LAQ824 with of HSP90 and the to with LAQ824 and the of misfolded and polyubiquitylated proteins in the also in K562 of HDAC6 acetylation and the chaperone function of K562 with the the that the siRNA to HDAC6 a the K562 expressing HDAC6 siRNA K562 with The levels of the to HSP90, with the with and with K562 expressing HDAC6 siRNA K562 with and the with K562 expressing HDAC6 siRNA K562 with the and the with the with The levels of the K562 expressing HDAC6 siRNA K562 with a of and LAQ824 the of by the The the of LAQ824 and LBH589 HSP90 acetylation in human leukemia and cells. of to LAQ824 of HSP90 by with that of HSP90 in a the levels of HSP90 to LBH589 a HSP90 acetylation with known to inhibit the of class induce HSP90 acetylation to the α-tubulin deacetylase of a in HSP90 of K562 with LAQ824 LBH589 HSP90 the with and the levels of HSP90 by and acetylation of HSP90 with binding of to HSP90 the analogue of the ATP binding of HSP90, also in the binding of to HSP90, with we the of the function of HSP90 a chaperone of K562 to LAQ824 the and the binding of to HSP90 to been with with LAQ824 the chaperone association of HSP90 to in the chaperone association also with LBH589 have shown that the in the chaperone association of the client proteins to the polyubiquitylation and of the client proteins in the the client proteins degradation by the with with LAQ824 in the by with the of K562 with LAQ824 the polyubiquitylation of proteins in the with polyubiquitylation of proteins also with with LAQ824 and with with LAQ824 the levels of in K562 also LAQ824 and AKT levels the levels of the α-tubulin and in a of the acetylation of α-tubulin and HSP90 by LAQ824 the that of HDAC6 be acetylation and of the chaperone function of we HDAC6 is co-immunoprecipitated with shown in in K562 HDAC6 be co-immunoprecipitated with with LAQ824 LBH589 with reduced the of HDAC6 that be co-immunoprecipitated with HSP90, by LAQ824 with a in the levels of the levels of to the of the ectopic overexpression of HDAC6 LAQ824-induced acetylation of α-tubulin and HSP90 and of in K562 cells. of HDAC6 in K562 cells, and the of and the overexpression of HDAC6 in with the K562 cells, a in HDAC6 in cells. The and a overexpression of HDAC6 be the its in the of in the levels in with the in the levels of α-tubulin of in LAQ824 HDAC6 in and cells. ectopic overexpression of HDAC6 also inhibited LAQ824-induced HSP90 acetylation in with the of LAQ824 in cells, a of and levels in demonstrate that HDAC6 a deacetylase α-tubulin also HSP90, we a siRNA to HDAC6 K562 to inhibit the of shown in with the in the HDAC6 levels by the siRNA to HDAC6 induced the acetylation of α-tubulin in K562 This to the of with HSP90 by with LAQ824 also levels with also induced the acetylation of HSP90, the levels of HSP90 HDAC6 is a deacetylase α-tubulin also HSP90 acetylation induced by HDAC6 the binding of ATP to HSP90, also with LAQ824 This that HSP90 acetylation in the chaperone function of HSP90, a also by the of of association of heat shock with HSP90 in to with acetylation and of HSP90 function of the chaperone association of with HSP90 shown in with polyubiquitylation of and depletion of the levels of Bcr-Abl, c-Raf, and the The of depletion of the client proteins is of in the levels of and of polyubiquitylation by the the client the of degradation of the client proteins by the a that in HDAC6 to the of misfolded proteins we the of polyubiquitylated and misfolded proteins induced by of the K562 and with LAQ824 that with LAQ824 induced in cells. This that the of the by aggresome to the of LAQ824 with of HSP90 and the to with LAQ824 and the of misfolded and polyubiquitylated proteins in the also in K562 been that with the LAQ824 and LBH589 the chaperone function of HSP90, polyubiquitylation and degradation of the pro-growth and pro-survival Bcr-Abl, c-Raf, and AKT proteins in human leukemia Here we have the that HDAC6 is the deacetylase HSP90, and depletion of HDAC6 levels and is to be and acetylation and of HSP90 a chaperone The of HDAC6 in HSP90 with and inhibit induce the acetylation of ATP binding of It also is a of the of HDAC6 and is to inhibit the of induced the acetylation of LAQ824 and LBH589 inhibitors that inhibit the class and also class IIB by the acetylation of a the predominantly HDAC6 to the class IIB This the of HDAC6 a deacetylase the ectopic overexpression of HDAC6 acetylation of α-tubulin also of It is that HDAC6 overexpression inhibit be to of by The also that HDAC6 is co-immunoprecipitated with HSP90 and that association is inhibited with LAQ824 LBH589 This the of the HDAC6 in binding and The also shown to be binding of HDAC6 to the and misfolded proteins. It also shown to be the aggresome the that the knock-down of HDAC6 acetylation of HSP90 the of HDAC6 HSP90 also demonstrate knock-down of HDAC6 of its by acetylation of HSP90 the of acetylation of HSP90 reduced the binding of HSP90 to ATP, to be a with reduced the chaperone association of HSP90 with its client proteins Bcr-Abl, its polyubiquitylation and in the This by with acetylation of HSP90 induced by HDAC6 depletion the levels of client proteins, e.g. Bcr-Abl. that a of HDAC6 to the depletion of pro-growth and pro-survival HSP90 client proteins the of the chaperone function of client protein is to a be the of the the the client proteins, the and of the client It be that the and acetylation of HSP90 the association of HSP90 with its is known to be by HSP90 is in the It also be to the HSP90 that in the in acetylation of that the ectopic overexpression and of HDAC6 with the acetylation of with that α-tubulin is a the of the of HDAC6 HDAC6 also been shown to with been shown to acetylation of α-tubulin with microtubule-associated proteins, and of HDAC6 of its the and of It that the of and induced the levels of misfolded and polyubiquitylated proteins and expressing leukemia the of with also been shown to in the we have to HDAC6 by depletion of HDAC6 levels by also the of This in of aggresome by in of misfolded proteins, aggresome and to the induced by misfolded proteins the that aggresome is of a to misfolded proteins and that HDAC6 a in the of the misfolded is that in with the of HDAC6 is with and that inhibit HDAC6 to the of misfolded proteins by HSP90 inhibitors to be It be to the of a protein is of the and in and It been that with the LAQ824 and LBH589 the chaperone function of HSP90, polyubiquitylation and degradation of the pro-growth and pro-survival Bcr-Abl, c-Raf, and AKT proteins in human leukemia Here we have the that HDAC6 is the deacetylase HSP90, and depletion of HDAC6 levels and is to be and acetylation and of HSP90 a chaperone The of HDAC6 in HSP90 with and inhibit induce the acetylation of ATP binding of It also is a of the of HDAC6 and is to inhibit the of induced the acetylation of LAQ824 and LBH589 inhibitors that inhibit the class and also class IIB by the acetylation of a the predominantly HDAC6 to the class IIB This the of HDAC6 a deacetylase the ectopic overexpression of HDAC6 acetylation of α-tubulin also of It is that HDAC6 overexpression inhibit be to of by The also that HDAC6 is co-immunoprecipitated with HSP90 and that association is inhibited with LAQ824 LBH589 This the of the HDAC6 in binding and The also shown to be binding of HDAC6 to the and misfolded proteins. It also shown to be the aggresome the that the knock-down of HDAC6 acetylation of HSP90 the of HDAC6 HSP90 also demonstrate knock-down of HDAC6 of its by acetylation of HSP90 the of acetylation of HSP90 reduced the binding of HSP90 to ATP, to be a with reduced the chaperone association of HSP90 with its client proteins Bcr-Abl, its polyubiquitylation and in the This by with acetylation of HSP90 induced by HDAC6 depletion the levels of client proteins, e.g. Bcr-Abl. that a of HDAC6 to the depletion of pro-growth and pro-survival HSP90 client proteins the of the chaperone function of client protein is to a be the of the the the client proteins, the and of the client It be that the and acetylation of HSP90 the association of HSP90 with its is known to be by HSP90 is in the It also be to the HSP90 that in the in acetylation of that the ectopic overexpression and of HDAC6 with the acetylation of with that α-tubulin is a the of the of HDAC6 HDAC6 also been shown to with been shown to acetylation of α-tubulin with microtubule-associated proteins, and of HDAC6 of its the and of It that the of and induced the levels of misfolded and polyubiquitylated proteins and expressing leukemia the of with also been shown to in the we have to HDAC6 by depletion of HDAC6 levels by also the of This in of aggresome by in of misfolded proteins, aggresome and to the induced by misfolded proteins the that aggresome is of a to misfolded proteins and that HDAC6 a in the of the misfolded is that in with the of HDAC6 is with and that inhibit HDAC6 to the of misfolded proteins by HSP90 inhibitors to be It be to the of a protein is of the and in and