Histone Deacetylase 6 Regulates Growth Factor-Induced Actin Remodeling and Endocytosis

Abstract

Histone deacetylase 6 (HDAC6) is a cytoplasmic deacetylase that uniquely catalyzes ␣-tubulin deacetylation and promotes cell motility. However, the mechanism underlying HDAC6-dependent cell migration and the role for microtubule acetylation in motility are not known. Here we show that HDAC6-induced global microtubule deacetylation was not sufficient to stimulate cell migration. Unexpectedly, in response to growth factor stimulation, HDAC6 underwent rapid translocation to actin-enriched membrane ruffles and subsequently became associated with macropinosomes, the vesicles for fluid-phase endocytosis. Supporting the importance of these associations, membrane ruffle formation, macropinocytosis, and cell migration were all impaired in HDAC6-deficient cells. Conversely, elevated HDAC6 levels promoted membrane ruffle formation with a concomitant increase in macropinocytosis and motility. In search for an HDAC6 target, we found that heat shock protein 90 (Hsp90), another prominent substrate of HDAC6, was also recruited to membrane ruffles and macropinosomes. Significantly, inhibition of Hsp90 activity suppressed membrane ruffling and cell migration, while expression of an acetylation-resistant Hsp90 mutant promoted ruffle formation. Our results uncover a surprising role for HDAC6 in actin remodeling-dependent processes and identify the actin cytoskeleton as an important target of HDAC6-regulated protein deacetylation.

CYLD mediates ciliogenesis in multiple organs by deubiquitinating Cep70 and inactivating HDAC6

“…Similarly, small-molecule inhibition of HDAC6 activity does not significantly affect the percentage of ciliated cells or ciliary length. These results are consistent with the findings that HDAC6 knockout mice are viable and fertile and develop normally, although they show hyperacetylated tubulin in many tissues [29,30]. It is possible that some redundancy exists in the regulation of ciliogenesis by tubulin deacetylases.…”

“…CYLD wild-type and knockout MEFs were isolated from E13.5 mouse embryos. HDAC6 wildtype and knockout MEFs were kindly provided by Dr Tso-Pang Yao (Duke University, USA) [30]. All MEFs were cultured in DMEM medium supplemented with 10% fetal bovine serum.…”

Limited efficacy of specific HDAC6 inhibition in urothelial cancer cells

“…It has therefore been proposed that HDAC6 expression per se but not its tubulin deacetylase activity is important for its effect on cell migration 56 and that these effects may be mediated by downstream factors like HSP90. 58 As high micromolar drug concentrations are impractical for clinical applications, we sought to find suitable combination regimens that would allow a dose reduction through synergistic effects. HDAC6 is involved in aggresome function, a cellular stress management system induced by misfolded proteins.…”

Cellular defence or viral assist: the dilemma of HDAC6

“…Cortical actin located immediately beneath the plasma membrane is the first obstacle encountered by the viruses upon infection, and reorganization of the cellular actin cytoskeleton significantly affects virus entry [72]. There is increasing evidence showing the connection between actin regulation and HDAC6 [73,74], and cortactin, an important regulator of actin assembly and disassembly, can also be tightly controlled by HDAC6 [24]. Furthermore, the antiviral effect of HDAC6 on virus entry and infection has been examined in vivo, which shows that HDAC6 overexpression significantly enhances resistance to avian H5N1 virus infection and extends the survival rate [75].…”