title: Cell-penetrating H4 tail peptides potentiate p53-mediated transactivation via inhibition of G9a and HDAC1.
abstract: Histone acetylation has a central role in establishing an active chromatin environment. The functional contribution of histone acetylation to chromatin transcription is accomplished by a dominant action of histone acetyltransferases over repressive histone-modifying activities at gene promoters; misregulation of these dynamic events can lead to various diseases. Here, we describe the synthesis and characterization of transducible peptides derived from histone H4 N-terminal tail as a molecular tool to establish and maintain the active state of p53 target genes. Cellular experiments demonstrate a distinct increase in p53 transactivation by acetylated H4 tail peptides, but only a modest change by unmodified H4 tail peptides. The molecular basis underlying the observed effects involves the selective interaction of the tail peptides with G9a histone methyltransferase and histone deacetylase 1 (HDAC1) and the disruption of their occupancy at p53 target promoters. Furthermore, treatment of xenograft models and cancer cell lines with the tail peptides sharply decline tumor cell growth and enhances apoptosis in response to DNA damage. These results indicate that H4 tail peptide mimics upregulate p53 transcription pathway and may be used as a novel strategy for anticancer therapy.
authors: Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA.
authors: K
authors: K
authors: Heo
authors: J-S
authors: JS
authors: Kim
authors: K
authors: K
authors: Kim
authors: H
authors: H
authors: Kim
authors: J
authors: J
authors: Choi
authors: K
authors: K
authors: Yang
authors: W
authors: W
authors: An
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002460:Cell Line / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D005260:Female; D016158:Genes, p53; D006649:Histocompatibility Antigens / Q000378:metabolism; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006657:Histones / Q000235:genetics*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009707:Nucleosomes / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology; D014158:Transcription, Genetic; D023041:Xenograft Model Antitumor Assays; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D057846:Cell-Penetrating Peptides; D006649:Histocompatibility Antigens; D006657:Histones; D009707:Nucleosomes; D011993:Recombinant Fusion Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1