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.
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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. "
ABSTRACT: Aberrant epigenetic repression of gene expression has been implicated in most cancers, including breast cancer. The nuclear amine oxidase, lysine-specific demethylase 1 (LSD1) has the ability to broadly repress gene expression by removing the activating mono- and di-methylation marks at the lysine 4 residue of histone 3 (H3K4me1 and me2). Additionally, LSD1 is highly expressed in estrogen receptor α negative (ER-) breast cancer cells. Since epigenetic marks are reversible, they make attractive therapeutic targets. Here we examine the effects of polyamine analog inhibitors of LSD1 on gene expression, with the goal of targeting LSD1 as a therapeutic modality in the treatment of breast cancer. Exposure of the ER-negative human breast cancer cells, MDA-MB-231 to the LSD1 inhibitors, 2d or PG11144, significantly increases global H3K4me1 and H3K4me2, and alters gene expression. Array analysis indicated that 98 (75 up and 23 down) and 477 (237 up and 240 down) genes changed expression by at least 1.5-fold or greater after treatment with 2d and PG11144, respectively. The expression of 12 up-regulated genes by 2d and 14 up-regulated genes by PG11144 was validated by quantitative RT-PCR. Quantitative chromatin immunoprecipitation (ChIP) analysis demonstrated that up-regulated gene expression by polyamine analogs is associated with increase of the active histone marks H3K4me1, H3K4me2 and H3K9act, and decrease of the repressive histone marks H3K9me2 and H3K27me3, in the promoter regions of the relevant target genes. These data indicate that the pharmacologic inhibition of LSD1 can effectively alter gene expression and that this therapeutic strategy has potential.Amino Acids 07/2011; 42(2-3):887-98. DOI:10.1007/s00726-011-1004-1 · 3.65 Impact Factor
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ABSTRACT: Esa1 (essential Sas2-related acetyltransferase 1) and Tip60 (HIV-1 TAT-interactive protein, 60 kDa) are key members of the MYST family of histone acetyltransferases (HATs) and play important functions in many cellular processes. In this work, we designed, synthesized and evaluated a series of substrate-based analogs for the inhibition of Esa1 and Tip60. The structures of these analogs feature that coenzyme A is covalently linked to the side chain amino group of the acetyl lysine residues in the histone peptide substrates. These bisubstrate analogs exhibit stronger potency in the inhibition of Esa1 and Tip60 compared to the small molecules curcumin and anacardic acid. In particular, H4K16CoA was tested as one of the most potent inhibitors for both Esa1 and Tip60. These substrate-based analog inhibitors will be useful mechanistic tools for analyzing biochemical mechanisms of Esa1 and Tip60, defining their functional roles in particular biological pathways, and facilitating protein crystallization and structural determination.Bioorganic & medicinal chemistry 02/2009; 17(3):1381-6. DOI:10.1016/j.bmc.2008.12.014 · 2.95 Impact Factor
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ABSTRACT: In the article by Bandyopadhyay et al. entitled “Spermidinyl-CoA-based HAT inhibitors block DNA repair and provide cancer-specific chemo- and radiosensitization,” which appeared in the September 1, 2009 issue of Cell Cycle (pp.2779-88), the first sentence in part (D) of the legend to Figure 3 appeared incorrectly as “(D) Inhibition of g-H2A.X acetylation by 1a: Top row - SDS-PAGE/Western of g-H2A.X in H358 cells treated with 10 µM CPT (1 hour) followed by incubation for an additional hour in the presence (right) or absence (left) of 50 µM 1a (60 µg/lane).” The correct sentence reads as follows: “(D) Inhibition of g-H2A.X acetylation by 1a: Top row - SDS-PAGE/Western of g-H2A.X in H358 cells treated with 5nM CPT (18 hours) in the presence (right lane) or absence (left lane) of 50 µM 1a (60 µg/lane).”Cell cycle (Georgetown, Tex.) 10/2009; 8(17):2779-88. DOI:10.4161/cc.9.5.11373 · 5.01 Impact Factor