P/CAF-mediated spermidine acetylation regulates histone acetyltransferase activity

Burgio, Giosalba; Corona, Davide; Nicotra, C; Carruba, Giuseppe; Taibi, Gennaro

doi:10.1080/14756366.2016.1205045

Cited by 11 publications

(10 citation statements)

References 39 publications

(46 reference statements)

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“…N 8 -acetylated spermidine was recently reported as a potential biomarker for SRS due to its elevated levels in the plasma of three SRS patients [28]. While the acetyltransferase responsible for this acetylation has yet to be definitively determined [29,30], it was recently found that deacetylation of N 8 -acetylspermidine to yield native spermidine is catalyzed by the cytoplasmic enzyme HDAC10 [31]. We therefore determined if HDAC10 expression levels were altered in the SRS lymphoblasts in our study.…”

Section: Resultsmentioning

confidence: 99%

Polyamine Homeostasis in Snyder-Robinson Syndrome

et al. 2018

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Loss-of-function mutations of the spermine synthase gene (SMS) result in Snyder-Robinson Syndrome (SRS), a recessive X-linked syndrome characterized by intellectual disability, osteoporosis, hypotonia, speech abnormalities, kyphoscoliosis, and seizures. As SMS catalyzes the biosynthesis of the polyamine spermine from its precursor spermidine, SMS deficiency causes a lack of spermine with an accumulation of spermidine. As polyamines, spermine, and spermidine play essential cellular roles that require tight homeostatic control to ensure normal cell growth, differentiation, and survival. Using patient-derived lymphoblast cell lines, we sought to comprehensively investigate the effects of SMS deficiency on polyamine homeostatic mechanisms including polyamine biosynthetic and catabolic enzymes, derivatives of the natural polyamines, and polyamine transport activity. In addition to decreased spermine and increased spermidine in SRS cells, ornithine decarboxylase activity and its product putrescine were significantly decreased. Treatment of SRS cells with exogenous spermine revealed that polyamine transport was active, as the cells accumulated spermine, decreased their spermidine level, and established a spermidine-to-spermine ratio within the range of wildtype cells. SRS cells also demonstrated elevated levels of tissue transglutaminase, a change associated with certain neurodegenerative diseases. These studies form a basis for further investigations into the leading biochemical changes and properties of SMS-mutant cells that potentially represent therapeutic targets for the treatment of Snyder-Robinson Syndrome.

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Section: Resultsmentioning

confidence: 99%

Polyamine Homeostasis in Snyder-Robinson Syndrome

et al. 2018

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“…So, altered levels of spermidine may affect the protein translation machinery and in particular levels of proline-rich proteins as one of eIF5α functions in translation elongation of polyproline stretches [71] which are abundant and critical for functioning of many signal transducing proteins [72]. Another feature of spermidine is its conversion into N 8 -acetylspermidine that is involved in regulation of histone acetylases [73].…”

Section: Discussionmentioning

confidence: 99%

Activation of Polyamine Catabolism by N1,N11-Diethylnorspermine in Hepatic HepaRG Cells Induces Dedifferentiation and Mesenchymal-Like Phenotype

Иванова

Snezhkina

Krasnov

et al. 2018

Cells

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Tumorigenesis is accompanied by the metabolic adaptation of cells to support enhanced proliferation rates and to optimize tumor persistence and amplification within the local microenvironment. In particular, cancer cells exhibit elevated levels of biogenic polyamines. Inhibitors of polyamine biosynthesis and inducers of their catabolism have been evaluated as antitumor drugs, however, their efficacy and safety remain controversial. Our goal was to investigate if drug-induced modulation of polyamine metabolism plays a role in dedifferentiation using differentiated human hepatocyte-like HepaRG cell cultures. N1,N11-diethylnorspermine (DENSpm), a potent inducer of polyamine catabolism, triggered an epithelial-mesenchymal transition (EMT)-like dedifferentiation in HepaRG cultures, as shown by down-regulation of mature hepatocytes markers and upregulation of classical EMT markers. Albeit the fact that polyamine catabolism produces H2O2, DENSpm-induced de-differentiation was not affected by antioxidants. Use of a metabolically stable spermidine analogue showed furthermore, that spermidine is a key regulator of hepatocyte differentiation. Comparative transcriptome analyses revealed, that the DENSpm-triggered dedifferentiation of HepaRG cells was accompanied by dramatic metabolic adaptations, exemplified by down-regulation of the genes of various metabolic pathways and up-regulation of the genes involved in signal transduction pathways. These results demonstrate that polyamine metabolism is tightly linked to EMT and differentiation of liver epithelial cells.

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“…Two major mechanisms for the modulation of histone acetylation have been reported. On the one hand, polyamines regulate the activity of various histone acetyltransferases (HATs) through direct and indirect means, including P300/CBP or P/CAF ( 39 – 42 ). Notably, in nontumoral settings, polyamine inhibition has been reported to increase H3K4 acetylation, which activates M1 differentiation of macrophages ( 43 ).…”

Section: Introductionmentioning

confidence: 99%