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Inhibition of HDAC6 Deacetylase Activity Increases Its Binding with Microtubules and Suppresses Microtubule Dynamic Instability in MCF-7 Cells

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Title Inhibition of HDAC6 Deacetylase Activity Increases Its Binding with Microtubules and Suppresses Microtubule Dynamic Instability in MCF-7 Cells
 
Creator ASTHANA, J
KAPOOR, S
MOHAN, R
PANDA, D
 
Subject KINETIC STABILIZATION
ALPHA-TUBULIN
IN-VIVO
ACETYLATION
ACETYLTRANSFERASE
STABILITY
MIGRATION
TRANSPORT
MOTILITY
 
Description The post-translational modification of tubulin appears to be a highly controlled mechanism that regulates microtubule functioning. Acetylation of the epsilon-amino group of Lys-40 of alpha-tubulin marks stable microtubules, although the causal relationship between tubulin acetylation and microtubule stability has remained poorly understood. HDAC6, the tubulin deacetylase, plays a key role in maintaining typical distribution of acetylated microtubules in cells. Here, by using tubastatin A, an HDAC6-specific inhibitor, and siRNA-mediated depletion of HDAC6, we have explored whether tubulin acetylation has a role in regulating microtubule stability. We found that whereas both pharmacological inhibition of HDAC6 as well as its depletion enhance microtubule acetylation, only pharmacological inhibition of HDAC6 activity leads to an increase in microtubule stability against cold and nocodazole-induced depolymerizing conditions. Tubastatin A treatment suppressed the dynamics of individual microtubules in MCF-7 cells and delayed the reassembly of depolymerized microtubules. Interestingly, both the localization of HDAC6 on microtubules and the amount of HDAC6 associated with polymeric fraction of tubulin were found to increase in the tubastatin A-treated cells compared with the control cells, suggesting that the pharmacological inhibition of HDAC6 enhances the binding of HDAC6 to microtubules. The evidence presented in this study indicated that the increased binding of HDAC6, rather than the acetylation per se, causes microtubule stability. The results are in support of a hypothesis that in addition to its deacetylase function, HDAC6 might function as a MAP that regulates microtubule dynamics under certain conditions.
 
Publisher AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
 
Date 2014-10-17T05:31:21Z
2014-10-17T05:31:21Z
2013
 
Type Article
 
Identifier JOURNAL OF BIOLOGICAL CHEMISTRY, 288(31)22516-22526
0021-9258
1083-351X
http://dx.doi.org/10.1074/jbc.M113.489328
http://dspace.library.iitb.ac.in/jspui/handle/100/16073
 
Language en