Histone deacetylase and 26S proteasome dual pathway (HDAC/26S Proteasome)

The combined inhibition of Histone Deacetylases (HDACs) and the 26S proteasome is a potent therapeutic strategy designed to disrupt protein homeostasis in cancer cells. HDACs are a class of enzymes that remove acetyl groups from histones and various non-histone proteins, influencing gene transcription and protein stability (UniProt). The 26S proteasome is a large ATP-dependent protease complex that serves as the primary machinery for degrading polyubiquitinated proteins (PubMed). In many cancers, particularly multiple myeloma, cells become highly dependent on these degradation pathways to clear misfolded or pro-apoptotic proteins. When the proteasome is inhibited, cells utilize the HDAC6-dependent aggresome pathway as a compensatory mechanism to transport misfolded proteins to lysosomes for degradation (NIH). By simultaneously blocking both the proteasome and HDACs, drugs induce massive accumulation of polyubiquitinated proteins, triggering severe proteotoxic stress and the unfolded protein response, which ultimately leads to programmed cell death (PubMed). This dual-targeting approach has been clinically validated through the combination of proteasome inhibitors like bortezomib with HDAC inhibitors like panobinostat to overcome drug resistance.

Other names

HDAC-Proteasome axisHDAC and Proteasome inhibitionAggresome-Proteasome pathway interactionCombined HDAC and UPS inhibition

Synergistic induction of proteotoxic stress and apoptosis through the simultaneous inhibition of the ubiquitin-proteasome system and the HDAC6-mediated aggresome protein degradation pathway (PubMed).