High levels of intracellular polyamines promote histone acetyltransferase activity resulting in chromatin hyperacetylation

Abstract

Polyamines stimulate expression of a variety of genes, including many implicated in cell proliferation. Indeed, aberrant expression of ornithine decarboxylase (ODC), a rate-limiting enzyme in polyamine biosynthesis, plays a causal role in tumorigenesis. Gene activity is influenced by dynamic changes in acetylation of nucleosomal histones. Although polyamines influence the histone acetyltransferase and deacetylase activities in cell-free systems, their ability to modulate these enzymes in live cells has never been established. To examine the effects of elevated intracellular levels of ODC and polyamines on gene transcription and histone acetylation, cells were infected with a retrovirus containing a cDNA for ODC. ODC overexpression potentiated the stimulatory effects of histone deacetylase inhibitors on reporter gene expression beyond that promoted by ODC or inhibitor treatment alone. Indeed, elevated intracellular levels of ODC promoted hyperacetylation of histones in several epidermal and fibroblast cell types. The ODC-mediated increase in acetylated histones was abrogated when cells were treated with alpha-difluoromethylornithine, a specific inhibitor of ODC activity, implying a distinct role for polyamines. Specifically, polyamines were found to enhance the action of histone acetyltransferases either directly or indirectly. Our studies document effects of elevated intracellular polyamine levels on histone acetylation in proliferating cells, suggesting a mechanism by which altered polyamine biosynthesis contributes to aberrant expression of genes, facilitating tumor growth. In addition, these studies may have implications for the development of drugs designed to regulate enzymes that modify the acetylation status of histones.

Proteome analysis in the assessment of ageing

“…Moreover, de novo protein biosynthesis will likely be affected by the decreases in the expression of eukaryotic translation initiation factor 2 subunit ␣ (eIF-2␣), glutamyl-prolyl-tRNA synthetase, and ribosomal protein L36. Reduced expression of spermidine synthase in aged ventral prostate, a key enzyme in polyamine metabolism, may further result in a heightened risk of chromatin instability and cancer as polyamines play a role in chromatin stability (Hobbs and Gilmour, 2000;Pollard et al, 1999) as well as cancer (Thomas and Thomas, 2003).…”

Autoimmune Diseases and Polyamines

“…This allows spermine to help stabilize chromatin structure and condense DNA in the nucleus [22]. In addition, spermine can stabilize DNA in alternate conformations, such as Z-DNA [23], and polyamines stimulate histone acetylation, which can alter epigenetic control of genes [24]. So, the importance of polyamine interactions with chromatin is evidenced by the requirement for polyamines in cell proliferation, DNA replication and repair, and transcription.…”

“…For example, elevated polyamine levels are seen in urine of patients with RA, SLE, and kidney dysfunction in diabetes [12,55,66]. Polyamines Table 1 Polyamine interactions Polyamines and chromatin Spermine aids in chromatin condensation and radioprotection of DNA [22] Polyamines stabilize alternate DNA forms (e.g., Z-DNA), modulating supercoils and loops [23] Polyamines stimulate histone acetylation [24] Polyamines alter conformation of nucleosome core particles [21,25] Polyamines aid DNA repair [26] Polyamines are involved in DNA replication [27] Polyamines are essential in translation Spermidine-lysine conjugate oxidized to hypusine in translational initiation factor eIF5A [28] Spermidine required for aminoacyl-tRNA-synthetase to charge tRNA [29] Translation efficiency improved with polyamines stabilizing tRNA conformation [30] Polyamines help ribosome assembly and stabilization in nucleolus [29] are elevated in skeletal muscles in myasthenia gravis [71], erythrocytes in diabetes [69], and in synovial tissue and fluid in RA [52]. With regards to RA, besides elevated polyamine levels, IL-1β induces elevated SSAT activity and increased putrescine in synovial cells in RA [11], which fits with the increased PAO activity seen in synovial fluid of RA patients [13].…”

X Chromosome Inactivation and Autoimmunity

“…The polyamines are ubiquitous small flexible cations that are essential for cell growth and proliferation [61,62]. Some putative functions and interactions attributed to polyamines of interest with regards to autoimmune diseases are stimulating histone acetylation [63]; increasing blood-brain and blood-nerve barrier permeability [64]; modulating ion channels [65]; modulating nuclear receptor interactions, such as increasing the affinity of estrogen receptor for DNA [66,67]; modulating DNA repair [68]; and stabilizing Z-DNA [69]. Because of the important interactions of polyamines, synthesis and recycling of polyamines are some of the most tightly controlled cellular processes (Fig.…”