Histone variants seem to play a major role in gene expression regulation. In
prostate cancer, H2A.Z and its acetylated form are implicated in oncogenes' upregulation.
SIRT1, which may act either as
tumor suppressor or oncogene, reduces H2A.Z levels in cardiomyocytes, via
proteasome-mediated degradation, and this mechanism might be impaired in
prostate cancer cells due to
sirtuin 1 downregulation. Thus, we aimed to characterize the mechanisms underlying H2A.Z and
SIRT1 deregulation in prostate
carcinogenesis and how they interact. We found that H2AFZ and
SIRT1 were up- and downregulated, respectively, at transcript level in primary
prostate cancer and high-grade
prostatic intraepithelial neoplasia compared to normal prostatic tissues. Induced
SIRT1 overexpression in
prostate cancer cell lines resulted in almost complete absence of H2A.Z. Inhibition of mTOR had a modest effect on H2A.Z levels, but
proteasome inhibition prevented the marked reduction of H2A.Z due to
sirtuin 1 overexpression.
Prostate cancer cells exposed to epigenetic modifying drugs
trichostatin A, alone or combined with
5-aza-2'-deoxycytidine, increased H2AFZ transcript, although with a concomitant decrease in
protein levels. Conversely,
SIRT1 transcript and
protein levels increased after exposure. ChIP revealed an increase of activation marks within the TSS region for both genes. Remarkably, inhibition of
sirtuin 1 with
nicotinamide, increased H2A.Z levels, whereas activation of
sirtuin 1 by
resveratrol led to an abrupt decrease in H2A.Z. Finally,
protein-
ligation assay showed that exposure to epigenetic modifying drugs fostered the interaction between
sirtuin 1 and H2A.Z. We concluded that
sirtuin 1 and H2A.Z deregulation in
prostate cancer are reciprocally related. Epigenetic mechanisms, mostly
histone post-translational modifications, are likely involved and impair
sirtuin 1-mediated downregulation of H2A.Z via
proteasome-mediated degradation. Epigenetic modifying drugs in conjunction with enzymatic modulators are able to restore the normal functions of
sirtuin 1 and might constitute relevant tools for targeted
therapy of
prostate cancer patients.