Objective: Androgen and its cognate, the androgen receptor (AR), play a critical role in the initiation and progression of prostate cancers.Recent studies revealed that epigenetic alterations such as histone methylation are involved in AR-mediated gene expression and associated with disease prognosis.We previously reported that PI3K p110beta is required for AR signaling.In this study, we assessed the global changes of histone H3 methylation after androgen stimulation in prostate cancer cells and determined the role of PI3K/p110beta activity in androgen-induced histone H3 methylation.Methods: Prostate cancer cell lines LAPC-4, LNCaP were cultured in methionine supplied and methionine deficient media respcetively.Histone H3 methylation status was assessed with specific antibody H3K4mel, H3K4me2, H3K4me3 in Western blot assay, total H3 and actin were used as protein loading control.LNCaP/sip110beta was stable transfected with siRNA of PI3K p110beta gene.EGF and R1881 were used to stimulate the growth singnal pathway and to detect the specifity of R1881 effect.Small chemical inhibitors (pan PI3K inhibitor:LY294002, p110 α inhibitor: PI103, TGX221:p110 β) were used to block PI3K activity.Other histone methylation status such as H3K9me2, H3K9me3, H3K27me2,H3K27me3, H3K36me2, H3K79me2 were also detected with pecific antibody.Results: In both LAPC-4 and LNCaP cells, global levels of histone H3K4 methylation largely were increased following treatment with a synthetic androgen R1881, which were in a time-dependent manner, the methylation status of H3K9, H3k27, H3k36 and H3k79 were not singnificantly changed.In contrast, treatment with a growth factor EGF did not induced a glossily elevation in histone H3 methylation.Interestingly, R1881-induced H3K4 methylation at di-and tri-levels were eliminated when cells were cultured in methionine-deficient media, suggesting it was a methyl transfering event.Finally,inhibitors for PI3K p110beta but not for p110a.pha suppressed androgen-induced di-and tri-methylation on H3K4, while p110alpha inhibition blocked H3K4 tri-methylation.Conclusion: Our data suggested that androgen increases the global levels of histone H3K4 methylation through a histone methyl transferase-dependent event.This event is dependent on PI3K p110beta activity, while p110alpha activity might be also involved in H3K4 tri-methylation.