title: KDM4B as a target for prostate cancer: structural analysis and selective inhibition by a novel inhibitor.
abstract: The KDM4/JMJD2 Jumonji C-containing histone lysine demethylases (KDM4A-KDM4D), which selectively remove the methyl group(s) from tri/dimethylated lysine 9/36 of H3, modulate transcriptional activation and genome stability. The overexpression of KDM4A/KDM4B in prostate cancer and their association with androgen receptor suggest that KDM4A/KDM4B are potential progression factors for prostate cancer. Here, we report the crystal structure of the KDM4B·pyridine 2,4-dicarboxylic acid·H3K9me3 ternary complex, revealing the core active-site region and a selective K9/K36 site. A selective KDM4A/KDM4B inhibitor, 4, that occupies three subsites in the binding pocket is identified by virtual screening. Pharmacological and genetic inhibition of KDM4A/KDM4B significantly blocks the viability of cultured prostate cancer cells, which is accompanied by increased H3K9me3 staining and transcriptional silencing of growth-related genes. Significantly, a substantial portion of differentially expressed genes are AR-responsive, consistent with the roles of KDM4s as critical AR activators. Our results point to KDM4 as a useful therapeutic target and identify a new inhibitor scaffold.
authors: Institute of Molecular and Cellular Biology and Department of Life Sciences and ‡Biomedical Science and Engineering Center, National Tsing-Hua University , Hsinchu, 30013, Taiwan.
authors: Chia-Han
authors: CH
authors: Chu
authors: Ling-Yu
authors: LY
authors: Wang
authors: Kai-Cheng
authors: KC
authors: Hsu
authors: Chung-Chin
authors: CC
authors: Chen
authors: Hsing-Hung
authors: HH
authors: Cheng
authors: Szu-Min
authors: SM
authors: Wang
authors: Chien-Ming
authors: CM
authors: Wu
authors: Tsan-Jan
authors: TJ
authors: Chen
authors: Ling-Ting
authors: LT
authors: Li
authors: Ruiwu
authors: R
authors: Liu
authors: Chiu-Lien
authors: CL
authors: Hung
authors: Jing-Moon
authors: JM
authors: Yang
authors: Hsing-Jien
authors: HJ
authors: Kung
authors: Wen-Ching
authors: WC
authors: Wang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C000592445:1,5-bis(2-(3,4-dichlorophenyl)ethenyl)-2,4-dinitrobenzene; D004791:Enzyme Inhibitors; D013267:Stilbenes; D056484:Jumonji Domain-Containing Histone Demethylases; C523637:KDM4B protein, human