Recurrent castration resistant prostate cancer remains a challenge for cancer therapies
and novel treatment options in addition to current anti-androgen and mitosis inhibitors
are needed. Aberrations in epigenetic enzymes and chromatin binding proteins have
been linked to prostate cancer and they may form a novel class of drug targets in the
future. In this thesis we systematically evaluated the epigenenome as a prostate cancer
drug target. We functionally silenced 615 known and putative epigenetically active
protein coding genes in prostate cancer cell lines using high throughput RNAi screening
and evaluated the effects on cell proliferation, androgen receptor (AR) expression and
histone patterns. Histone deacetylases (HDACs) were found to regulate AR expression.
Furthermore, HDAC inhibitors reduced AR signaling and inhibited synergistically
with androgen deprivation prostate cancer cell proliferation. In particular, TMPRSS2-
EGR fusion gene positive prostate cancer cell lines were sensitive to combined HDAC
and AR inhibition, which may partly be related to the dependency of a fusion gene
induced epigenetic pathway. Histone demethylases (HDMs) were identified to regulate
prostate cancer cell line proliferation. We discovered a novel histone JmjC-domain
histone demethylase PHF8 to be highly expressed in high grade prostate cancers and
mediate cell proliferation, migration and invasion in in vitro models. Additionally, we
explored novel HDM inhibitor chemical structures using virtual screening methods.
The structures best fitting to the active pocket of KDM4A were tested for enzyme
inhibition and prostate cancer cell proliferation activity in vitro. In conclusion, our
results show that prostate cancer may efficiently be targeted with combined AR and
HDAC inhibition which is also currently being tested in clinical trials. HDMs were
identified as another feasible novel drug target class. Future studies in representative
animal models and development of specific inhibitors may reveal HDMs full potential
in prostate cancer therapySiirretty Doriast
