Histone deacetylase–proteasome pathway axis (HDAC–UPS axis) (HDAC–UPS axis)

The Histone deacetylase (HDAC)–proteasome pathway axis is a critical regulatory network that maintains cellular protein homeostasis (proteostasis) by coordinating protein degradation and gene expression. This axis primarily involves the ubiquitin-proteasome system (UPS), which degrades short-lived and misfolded proteins, and the HDAC6-mediated aggresome pathway, which serves as a compensatory mechanism when the proteasome is overwhelmed (Hideshima et al., 2005, PubMed). In malignant cells, particularly in multiple myeloma, the high rate of protein synthesis creates a dependency on these degradation pathways to prevent the toxic accumulation of misfolded proteins (Nawrocki et al., 2006, PubMed). Therapeutic strategies targeting this axis often utilize a combination of proteasome inhibitors, such as bortezomib, and HDAC inhibitors, such as panobinostat, to induce catastrophic proteotoxic stress and apoptosis (Richardson et al., 2013, Lancet Oncology). This dual inhibition is particularly effective because it blocks both the primary and the backup protein disposal systems, overcoming resistance mechanisms observed with single-agent therapies. Beyond oncology, this axis is also investigated in neurodegenerative diseases where protein aggregation is a hallmark, though therapeutic applications there focus on different modulatory outcomes (Simões-Pires et al., 2013, Molecular Neurobiology). The clinical success of targeting this axis is evidenced by the FDA approval of panobinostat in combination with bortezomib for relapsed multiple myeloma.

Other names

HDAC-proteasome axisHDAC-UPS pathwayHistone deacetylase-ubiquitin proteasome system axisAggresome-proteasome axis

Dual inhibition of the ubiquitin-proteasome system and the HDAC6-mediated aggresome pathway to induce synergistic proteotoxic stress and apoptosis.