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Cell-penetrating H4 tail peptides potentiate p53-mediated transactivation via inhibition of G9a and HDAC1

Oncogene volume 32, pages 2510–2520 (2013)Cite this article

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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.

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Acknowledgements

We thank Dr Michael Stallcup and Mr Dan Gerke for the gift of pSG5-FLAG-G9a and G9a shRNA constructs. The technical assistance of Drs Balachandra Hegde and Ralph Langen in circular dichroism analysis is greatly acknowledged. We also thank Dr Jing Huang for p53K373me2 antibody. This work was supported by R01GM84209 to WA from the National Institutes of Health, RSG DMC1005001 to WA from the American Cancer Society and DIRAMS (50595-2012) to KH from the Ministry of Education, Science and Technology.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, CA, Los Angeles, USA

    K Heo, K Kim, H Kim, J Choi & W An

  2. Research Center, Dongnam Institute of Radiological and Medical Sciences (DIRAMS), Busan, Korea

    K Heo, J-S Kim & K Yang

  3. Department of Pediatric Oncology, Division of Hematology/Oncology, Department of Pediatrics, Dana-Farber Cancer Institute, Children’s Hospital Boston, Harvard Medical School, MA, Boston, USA

    H Kim

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  1. K Heo
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Correspondence to W An.

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Heo, K., Kim, JS., Kim, K. et al. Cell-penetrating H4 tail peptides potentiate p53-mediated transactivation via inhibition of G9a and HDAC1. Oncogene 32, 2510–2520 (2013). https://doi.org/10.1038/onc.2012.273

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