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The KDM4/JMJD2 Jumonji C-containing histone lysine demethylases (KDM4A-D) that selectively remove the methyl group (s) from tri/di-methylated lysine 9/36 of histone H3 play a key role in diverse cellular processes including transcriptional activation, genome stability and carcinogenesis.KDM4B is overexpressed in several type of cancer including prostate, breast, and gastric cancer and promotes cancer cell growth.Further, KDM4B functions as a co-activator of androgen receptor, estrogen receptor and beta-catenin to regulate transcriptional effects.Here, we show that KDM4B is up-regulated under hypoxia and Helicobacter pylori treatment.Interestingly, H.pylori-induced chemokine production was mediated by KDM4B but not KDM4A and KDM4C.Overexpression of KDM4B triggers c-Jun-mediated transcriptional activity while genetic knockdown reduced the effect.We have also determined the crystal structure of the KDM4B·PD2 (2,4-dicarboxylic acid) ·H3K9me3 ternary complex that reveals the core active-site region and selective K9/K36 substrate site.Structure-guided approach identifies selective KDM4B inhibitors NSCB 1 and NSCM1 that occupy both the consensus and specific sites.Further, pharmacological and genetic inhibition of KDM4B significantly blocks viability of cultured prostate cancer cells.Such an inhibition is accompanied by increased methylation of H3K9 and transcriptional reprogramming of genes in cell growth and genomic stability.Strikingly, a significant portion of NSCB1 altered genes are AR-responsive, consistent with KDM4Bs roles as critical coactivator of AR.Our results together prove KDM4B as a useful therapeutic target of tumors driven by enhanced KDM4B activity and demonstrate selective inhibitors for further structure-activity-relationship studies.