Posttranslational modification and beyond: interplay between histone deacetylase 6 and heat-shock protein 90.

Posttranslational modification (PTM) and regulation of protein stability are crucial to various biological processes. Histone deacetylase 6 (HDAC6), a unique histone deacetylase with two functional catalytic domains (DD1 and DD2) and a ZnF-UBP domain (ubiquitin binding domain, BUZ), regulates a number of biological processes, including gene expression, cell motility, immune response, and the degradation of misfolded proteins. In addition to the deacetylation of histones, other nonhistone proteins have been identified as substrates for HDAC6. Hsp90, a molecular chaperone that is a critical modulator of cell signaling, is one of the lysine deacetylase substrates of HDAC6. Intriguingly, as one of the best-characterized regulators of Hsp90 acetylation, HDAC6 is the client protein of Hsp90. In addition to regulating Hsp90 at the post-translational modification level, HDAC6 also regulates Hsp90 at the gene transcription level. HDAC6 mainly regulates the Hsp90-HSF1 complex through the ZnF-UBP domain, thereby promoting the HSF1 entry into the nucleus and activating gene transcription. The mutual interaction between HDAC6 and Hsp90 plays an important role in the regulation of protein stability, cell migration, apoptosis and other functions. Plenty of of studies have indicated that blocking HDAC6/Hsp90 has a vital regulatory role in multifarious diseases, mainly in cancers. Therefore, developing inhibitors or drugs against HDAC6/Hsp90 becomes a promising development direction. Herein, we review the current knowledge on molecular regulatory mechanisms based on the interaction of HDAC6 and Hsp90 and inhibition of HDAC6 and/or Hsp90 in oncogenesis and progression, antiviral and immune-related diseases and other vital biological processes.