title: KDM4B/JMJD2B is a p53 target gene that modulates the amplitude of p53 response after DNA damage.
abstract: The p53 tumor suppressor protein plays a critical role in orchestrating the genomic response to various stress signals by acting as a master transcriptional regulator. Differential gene activity is controlled by transcription factors but also dependent on the underlying chromatin structure, especially on covalent histone modifications. After screening different histone lysine methyltransferases and demethylases, we identified JMJD2B/KDM4B as a p53-inducible gene in response to DNA damage. p53 directly regulates JMJD2B gene expression by binding to a canonical p53-consensus motif in the JMJD2B promoter. JMJD2B induction attenuates the transcription of key p53 transcriptional targets including p21, PIG3 and PUMA, and this modulation is dependent on the catalytic capacity of JMJD2B. Conversely, JMJD2B silencing led to an enhancement of the DNA-damage driven induction of p21 and PIG3. These findings indicate that JMJD2B acts in an auto-regulatory loop by which p53, through JMJD2B activation, is able to influence its own transcriptional program. Functionally, exogenous expression of JMJD2B enhanced subcutaneous tumor growth of colon cancer cells in a p53-dependent manner, and genetic inhibition of JMJD2B impaired tumor growth in vivo. These studies provide new insights into the regulatory effect exerted by JMJD2B on tumor growth through the modulation of p53 target genes.
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Castellini
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Eui Jung
authors.initials: EJ
authors.lastname: Moon
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA 92697, USA.
authors.forename: Olga V
authors.initials: OV
authors.lastname: Razorenova
authors.affiliation: Department of Obstetrics and Gynecology, Oregon Health and Sciences University, Portland, OR 97239, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Krieg
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Rie
authors.initials: R
authors.lastname: von Eyben
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Amato J
authors.initials: AJ
authors.lastname: Giaccia
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004249:DNA Damage; D044127:Epigenesis, Genetic; D056466:Histone Demethylases / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009153:Mutagens / Q000633:toxicity; D009369:Neoplasms / Q000473:pathology; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D009153:Mutagens; D016159:Tumor Suppressor Protein p53; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C523637:KDM4B protein, human; D011495:Histone-Lysine N-Methyltransferase