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.

journal_name

Oncogene

journal_title

Oncogene

authors

Heo K,Kim JS,Kim K,Kim H,Choi J,Yang K,An W

doi

10.1038/onc.2012.273

subject

Has Abstract

pub_date

2013-05-16 00:00:00

pages

2510-20

issue

20

eissn

0950-9232

issn

1476-5594

pii

onc2012273

journal_volume

32

pub_type

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