Androgen receptor (AR) plays pivotal roles in
prostate cancer. Upon
androgen stimulation, AR recruits the
Protein kinase N1 (PKN1), which phosphorylates
histone H3 at
threonine 11, with subsequent recruitment of
tryptophan,
aspartic acid (WD) repeat-containing
protein 5 (WDR5) and the
su(var)3-9, enhancer of zeste, trithorax/mixed-lineage
leukemia (SET1/MLL)
histone methyltransferase complex to promote AR target gene activation and
prostate cancer cell growth. However, the underlying mechanisms of target gene activation and cell growth subsequent to WDR5 recruitment are not well understood. Here, we demonstrate an epigenetic cross talk between histone modifications and AR target gene regulation. We discovered that
K(lysine) acetyltransferase 8 (KAT8), a member of the MOZ, YBF2/SAS2, and TIP 60
protein 1 (MYST) family of
histone acetyltransferases that catalyzes
histone H4 lysine 16 acetylation, colocalized with WDR5 at AR target genes, resulting in
hormone-dependent gene activation in
prostate cancer cells. PKN1 or WDR5 knockdown severely inhibited KAT8 association with AR target genes and
histone H4 lysine 16 acetylation upon
androgen treatment. Knockdown of KAT8 significantly decreased AR target gene expression and
prostate cancer cell proliferation. Collectively, these data describe a trans-
histone modification pathway involving PKN1/
histone H3 threonine 11 phosphorylation followed by WDR5/MLL
histone methyltransferase and KAT8/
histone acetyltransferase recruitment to
effect androgen-dependent gene activation and
prostate cancer cell proliferation.