title: KDM4/JMJD2 Histone Demethylase Inhibitors Block Prostate Tumor Growth by Suppressing the Expression of AR and BMYB-Regulated Genes.
abstract: Histone lysine demethylase KDM4/JMJD2s are overexpressed in many human tumors including prostate cancer (PCa). KDM4s are co-activators of androgen receptor (AR) and are thus potential therapeutic targets. Yet to date few KDM4 inhibitors that have anti-prostate tumor activity in vivo have been developed. Here, we report the anti-tumor growth effect and molecular mechanisms of three novel KDM4 inhibitors (A1, I9, and B3). These inhibitors repressed the transcription of both AR and BMYB-regulated genes. Compound B3 is highly selective for a variety of cancer cell lines including PC3 cells that lack AR. B3 inhibited the in vivo growth of tumors derived from PC3 cells and ex vivo human PCa explants. We identified a novel mechanism by which KDM4B activates the transcription of Polo-like kinase 1 (PLK1). B3 blocked the binding of KDM4B to the PLK1 promoter. Our studies suggest a potential mechanism-based therapeutic strategy for PCa and tumors with elevated KDM4B/PLK1 expression.
authors.affiliation: Departments of Internal Medicine and Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Lingling
authors.initials: L
authors.lastname: Duan
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Ganesha
authors.initials: G
authors.lastname: Rai
authors.affiliation: Department of Biophysics, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry and Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Roggero
authors.affiliation: Departments of Internal Medicine and Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Qing-Jun
authors.initials: QJ
authors.lastname: Zhang
authors.affiliation: Departments of Internal Medicine and Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Department of Urology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Shi Hong
authors.initials: SH
authors.lastname: Ma
authors.affiliation: Department of Clinical Science, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Urology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: John
authors.initials: J
authors.lastname: Santoyo
authors.affiliation: Department of pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Elisabeth D
authors.initials: ED
authors.lastname: Martinez
authors.affiliation: Department of Clinical Science, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Guanghua
authors.initials: G
authors.lastname: Xiao
authors.affiliation: Department of Urology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Ganesh V
authors.initials: GV
authors.lastname: Raj
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Ajit
authors.initials: A
authors.lastname: Jadhav
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Maloney
authors.affiliation: Department of Biophysics, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry and Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Josep
authors.initials: J
authors.lastname: Rizo
authors.affiliation: Department of Urology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jer-Tsong
authors.initials: JT
authors.lastname: Hsieh
authors.affiliation: Departments of Internal Medicine and Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: zhi-ping.liu@utsouthwestern.edu.
authors.forename: Zhi-Ping
authors.initials: ZP
authors.lastname: Liu
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D011944:Receptors, Androgen / Q000096:biosynthesis* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D056484:Jumonji Domain-Containing Histone Demethylases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen; D000097869:Polo-Like Kinase 1; C410798:AR protein, human; C523637:KDM4B protein, human