| dc.description.abstract |
<p>The androgen receptor (AR) signaling axis is a well-established therapeutic target
in prostate cancer, due to its central role in tumor maintenance and progression.
Although patients respond initially to androgen deprivation therapies and AR antagonists,
they invariably progress to a castration-resistant state. Consequently, there is
an unmet need for agents that target the AR signaling axis in a unique manner. </p><p>Histone
deacetylase (HDAC) inhibitors repress AR signaling and prostate cancer growth in cellular
and xenograft models. However, HDAC inhibitors also induce epithelial to mesenchymal
(EMT) and neuroendocrine differentiation, both of which are associated with prostate
cancer progression and aggressiveness. Given that 18 different HDAC isoforms have
been identified in humans, and non-selective or Class I (HDAC1, 2, 3, and 8) HDAC
inhibitors have been used in most of these studies, the relative contribution of individual
HDAC isoforms to AR transcriptional activity and prostate cancer pathophysiology remains
to be elucidated. The overarching goals of this study were to (1) determine the role
of individual Class I HDACs in AR transcriptional activity and prostate cancer growth,
(2) identify selective HDAC inhibitors that have reduced adverse profiles to the treatment
of prostate cancer, and (3) identify potential HDAC-interacting proteins that regulate
AR target gene transcription and prostate cancer growth. </p><p>Using genetic knockdown
studies and pharmacological inhibitors with isoform selectivity, we identified that
HDAC3 was required for AR transcriptional activity and proliferation in cellular models
of androgen-sensitive and castration-resistant prostate cancer (CRPC). Additionally,
we found that RGFP966, an HDAC3-selective inhibitor, attenuated the growth of a xenograft
model of CRPC. Furthermore, non-selective HDAC inhibitors induced EMT and neuroendocrine
markers in prostate cancer cells, but RGFP966 treatment did not. These studies provide
rationale for selective inhibition of HDAC3 for the treatment of CRPC, and could provide
an explanation for the lack of success using non-selective HDAC inhibitors in clinical
trials for prostate cancer.</p><p>We also assessed the role of REV-ERB alpha, an HDAC3-interacting
protein, in the regulation of AR transcriptional activity and prostate cancer growth.
Using siRNA knockdown studies, REV-ERB inhibitors, and overexpression studies, we
concluded that REV-ERB alpha; was required for AR target gene induction and prostate
cancer growth, including models of CRPC. These studies also provide rational for targeting
REV-ERB alpha; for the treatment of CRPC.</p><p>Taken together, these studies identify
two novel targets in the HDAC signaling axis for the treatment of prostate cancer:
HDAC3 and REV-ERB alpha. Our studies provide greater insight into AR transcriptional
regulation and prostate cancer pathophysiology.</p>
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