Polyamine-mediated regulation of protein acetylation in murine skin and tumors

Lankenau Institute for Medical Research, Wynnewood, Pennsylvania 19096, USA.
Molecular Carcinogenesis (Impact Factor: 4.77). 08/2007; 46(8):611-7. DOI: 10.1002/mc.20350
Source: PubMed

ABSTRACT Overexpression of ornithine decarboxylase (ODC), resulting in increased polyamine metabolism, is a common feature of epithelial tumors. Polyamines play a complex role in promoting tumor development, affecting diverse cellular processes, including gene expression. One way polyamines may affect gene expression is to modulate the multiprotein complexes comprised of transcription factors and coregulatory factors that alter chromatin structure by acetylating/deacetylating nearby histones. We have capitalized on ODC-overexpressing cultured cells and K6/ODC and ODC/Ras transgenic mouse models, in which ODC overexpression is targeted to hair follicles, to evaluate the influence of polyamines on the acetylation of histones and other proteins. ODC overexpression was found to alter intrinsic histone acetyltransferase (HAT) and deacetylase activities and histone acetylation patterns. The high HAT activity exhibited by ODC transgenic mouse skin and tumors might be partly attributed to enhanced p300/creb-binding protein (CBP)-associated HAT activity and increased levels of Tat interactive protein, 60 kDa (Tip60) HAT protein isoforms. Altered association of Tip60 with E2F1 and a subset of newly identified Tip60-interacting transcription factors was detected in ODC mouse skin and tumors, implying novel polyamine modulation of Tip60-regulated gene expression. Polyamine effects on HAT enzymes also influence the acetylation status of nonhistone proteins. Overexpression of ODC in skin serves as a novel stimulus for acetylation of the tumor suppressor protein, p53--a target of both p300/CBP and Tip60--with concomitant increased binding to, and increased transcription of, a downstream target gene. The future challenge will be to elucidate the multiple mechanisms by which polyamines influence enzymes that regulate protein acetylation and gene transcription to promote cancer.

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    • "That alterations in polyamine or polyamine analogue content can affect changes in chromatin has been well established. Gilmour and colleagues (Hobbs and Gilmour 2000; Hobbs et al. 2002; Hobbs et al. 2003; Hobbs et al. 2006; Wei et al. 2007) have demonstrated that changes in polyamines can lead to significant changes in chromatin acetylation. More importantly, the oligoamines have been shown to be potent inducers of nucleosomal array oligomerization (Carruthers et al. 2007), thus emphasizing their potential for direct effects on chromatin in addition to inhibition of LSD1. "
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