Linking HDAC and Proteasome Inhibition

Histone deacetylase inhibitors (HDACIs), including vorinostat, which has recently been approved for the treatment of cutaneous T-cell lymphoma, represent prototypes of agents that act through epigenetic mechanisms. It has generally been assumed that such agents act by acetylating the positively charged histone tails of nucleosomes, leading to a more relaxed chromatin structure and transcription of genes that induce cell differentiation or death. However, it has become apparent that HDACIs act through diverse mechanisms to induce cell death, including some related to acetylation of non-histone proteins. For example, HDACI-mediated cell death has been attributed to induction of oxidative injury, up-regulation of death receptors, disruption of chaperone function, increased expression of pro-death proteins (e.g., Bim), interference with DNA repair proteins, and abrogation of cell-cycle checkpoints, among numerous others.

 In addition to these actions, HDACIs have also been reported to disrupt proteasome function,¹ although the mechanism by which this phenomenon occurs is uncertain. One possibility is that HDACIs, at least those that inhibit HDAC6 and act as tubulin acetylases, interfere with the function of aggresomes involved in the disposition of excess proteins targeted for proteasomal degradation.²  It is postulated that disruption of proteasome function (e.g., by proteasome inhibitors) can amplify the lethal consequences of these events. Notably, regimens combining HDACI with proteasome inhibitors have recently shown significant promise in the treatment of multiple myeloma and have elicited responses in some patients who have progressed following prior proteasome inhibitor therapy. Thus, the link between HDACI activity and proteasome function has clear therapeutic implications.

 Despite these insights, the precise mechanism by which HDACIs disrupt proteasome function has remained elusive. The results of the recent study by Fotheringham et al. may shed light on this important question. Using a loss-of-function screen involving a short inhibitory RNA library directed against a broad array of genes, the authors identified HR23B, a protein involved in both nucleotide excision repair and targeting cargo proteins to the proteasome, as a critical determinant of HDACI sensitivity in U20S human osteosarcoma cells. Notably, HDACIs resulted in HR23B acetylation and accumulation as well as diminished proteasome activity; moreover, siRNA directed against HR23B attenuated both HDACI-mediated proteasome inhibition and cell death induction. The pro-apoptotic role of HR23B-treated cells was found to be related to its capacity to shuttle cargo proteins to the proteasome but not to DNA repair functions. Interestingly, proteasome inhibitors also caused HR23B accumulation and, as in the case of HDACIs, knock down of HR23B protected cells from proteasome inhibitor lethality. Collectively, these findings raise the possibility that HDAC and proteasome inhibitors may act through overlapping pathways converging on HR23B-mediated disruption of proteasome function. Interestingly, HR23B levels were found to be highly expressed in malignant T cells, which may explain, in part, the sensitivity of such cells to HDACIs.