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

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.

Arginase 1 and arginase 2 variations associate with asthma, asthma severity and β2 agonist and steroid response

“…As mentioned, increased arginase activity induced by allergen challenge promotes the formation of peroxynitrite through uncoupling of iNOS [2,8], which could subsequently lead to the inactivation of HDAC2. In addition, arginase may also affect histone acetylation through the production of polyamines, which are known to promote HAT activity and chromatin hyperacetylation [43].…”

Oligoamine analogues in combination with 2-difluoromethylornithine synergistically induce re-expression of aberrantly silenced tumour-suppressor genes

“…Increased intracellular polyamines have been implicated in alterations in histone acetyltransferases and HDACs, potentially resulting in epigenetic changes that lead to the initiation and progression of tumours in a transgenic mouse model where ODC, the target of DFMO, is overexpressed [44–46]. Another previous report indicates that polyamine depletion by DFMO can induce differentiation in cardiac myocytes through epigenetic mechanisms [47].…”

Polyamine analogs modulate gene expression by inhibiting lysine-specific demethylase 1 (LSD1) and altering chromatin structure in human breast cancer cells

“…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.…”