Histone deacetylase 6 (HDAC6) (HDAC6)

Histone deacetylase 6 (HDAC6) is a Class IIb enzyme primarily located in the cytoplasm, distinguished by its two catalytic domains and a C-terminal zinc-finger ubiquitin-binding domain (ZnF-UBP) (UniProt: Q9UBN7). It plays a pivotal role in cellular protein homeostasis by coordinating the clearance of misfolded, ubiquitinated proteins. When the primary proteasomal degradation pathway is impaired or saturated, HDAC6 facilitates the transport of these proteins along microtubules to the aggresome for subsequent degradation via autophagy (Kawaguchi et al., 2003). This "backup" role makes HDAC6 a significant therapeutic target in cancers like multiple myeloma, where its inhibition can synergize with proteasome inhibitors to induce lethal proteotoxic stress (Hideshima et al., 2005). Additionally, HDAC6 regulates diverse cellular processes such as microtubule stability, cell motility, and immune response by deacetylating non-histone substrates like alpha-tubulin and Hsp90 (Hubbert et al., 2002). Therapeutic strategies include small-molecule inhibitors like ricolinostat and emerging proteolysis-targeting chimeras (PROTACs) designed to degrade the protein entirely (Yang et al., 2020). Beyond oncology, HDAC6 is investigated for its role in neurodegenerative diseases and inflammatory conditions due to its impact on axonal transport and immune cell function. The development of selective HDAC6 inhibitors aims to reduce the toxicities associated with pan-HDAC inhibition while maintaining therapeutic efficacy.

Other names

HDAC6Histone deacetylase 6CPBPHD6JM21PPP1R90

Inhibition of HDAC6 catalytic activity; Targeted protein degradation via PROTACs; Synergistic inhibition of the aggresome-autophagy pathway