Histone methylation is a dynamic process that participates in a diverse array of cellular processes.Several histone demethylases have been recently identified,but demethylases for the trimethylated lysine 4 on histone 3 (H3K4me3) is still elusive.It is also not known if a histone demethylase exists that is capable of removing tri-,di-,and monomethyl groups from a specific lysine.Through bioinformatic and biochemical analysis,we identified JARID1B as a H3K4 demethylase.Overexpression of JARID1B resuited in loss of tri-,di-,and monomethyl H3K4,but did not affect other histone lysine methylation.In vitro biochemical experiments demonstrated that JARID1B directly catalyzes the demethylation and the enzymatic activity requires the JmjC domain and Fe(Ⅱ) and a-ketoglutamate as cofactors.We also showed that JARID1B associates with androgen receptor and regulated its transcriptional activity.Furthermore,we demonstrated that JARID1B is upregulated in prostate cancer.Thus,we identify JARID1B as a demethytase capable of removing three methyl groups from histone 3 lysine 4 and as a potential thera-peutic target for prostate cancer.