By Steven Grant, MD
2009-07-01
Dr. Grant indicated no relevant conflicts of interest.
Fotheringham S, Epping MT, Stimson L et al. Genome-wide loss-of-function screen reveals an important role for the proteasome in HDAC inhibitor-induced apoptosis. Cancer Cell. 2009;15:57-66.
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.
The significance of this study is that increased
HR23B expression may represent a novel biomarker capable of predicting
whether a particular tumor type (e.g., CTCL) or an individual patient’s
tumor will respond to HDACI therapy. The results of this study also
provide new insights into a possible mechanism by which HDACIs, among
their numerous actions, interfere with proteasome function. Finally,
these findings may have implications for attempts to understand the
basis for synergistic interactions between HDAC and proteasome
inhibitors, a strategy that has shown significant promise in indolent
B-cell malignancies such as multiple myeloma. In light of these
findings, efforts to document the functional significance of HR23B in
HDACI-mediated lethality toward CTCL and other malignant human
hematopoietic cells will be of the highest priority.
Mitsiades CS, Mitsiades NS, McMullan CJ et al. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci USA. 2004;101:540-5.
Hideshima T, Bradner JE, Wong J et al. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci USA. 2005;102:8567-72.
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