bims-polyam 2024-07-21 papers

Issue of 2024‒07‒21
six papers selected by
Sebastian J. Hofer, University of Graz

bioRxiv. 2024 Jul 02. pii: 2024.07.02.600738. [Epub ahead of print]

Polyamines regulate cell fate by altering the activity of histone-modifying enzymes.

Maya Emmons-Bell, Grace Forsyth, Abby Sundquist, Sylvie Oldeman, Angeliki Gardikioti, Roshni de Souza, Jonathan Coene, Maryam H Kamel, Shine Ayyapan, Harrison A Fuchs, Steven Verhelst, Joanna Smeeton, Catherine A Musselman, Juan-Manuel Schvartzman.

Polyamines are polycationic alkyl-amines abundant in proliferating stem and cancer cells. How these metabolites influence numerous cellular functions remains unclear. Here we show that polyamine levels decrease during differentiation and that inhibiting polyamine synthesis leads to a differentiated-like cell state. Polyamines concentrate in the nucleus and are further enriched in the nucleoli of cells in culture and in vivo . Loss of polyamines drives changes in chromatin accessibility that correlate with altered histone post-translational modifications. Polyamines interact electrostatically with DNA on the nucleosome core, stabilizing histone tails in conformations accessible to modifying enzymes. These data reveal a mechanism by which an abundant metabolite influences chromatin structure and function in a non-sequence specific manner, facilitating chromatin remodeling during reprogramming and limiting it during fate commitment.

DOI: https://doi.org/10.1101/2024.07.02.600738

J Pathol. 2024 Jul 18.

Increased hepatic putrescine levels as a new potential factor related to the progression of metabolic dysfunction-associated steatotic liver disease.

María Ángeles Núñez-Sánchez, María Antonia Martínez-Sánchez, Marta Sierra-Cruz, Ana Lambertos, Sara Rico-Chazarra, Alba Oliva-Bolarín, Andrés Balaguer-Román, José Enrique Yuste, Carlos Manuel Martínez, Adriana Mika, María Dolores Frutos, Camilo J Llamoza-Torres, José Córdoba-Chacón, Bruno Ramos-Molina.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver condition that often progresses to more advanced stages, such as metabolic dysfunction-associated steatohepatitis (MASH). MASH is characterized by inflammation and hepatocellular ballooning, in addition to hepatic steatosis. Despite the relatively high incidence of MASH in the population and its potential detrimental effects on human health, this liver disease is still not fully understood from a pathophysiological perspective. Deregulation of polyamine levels has been detected in various pathological conditions, including neurodegenerative diseases, inflammation, and cancer. However, the role of the polyamine pathway in chronic liver disorders such as MASLD has not been explored. In this study, we measured the expression of liver ornithine decarboxylase (ODC1), the rate-limiting enzyme responsible for the production of putrescine, and the hepatic levels of putrescine, in a preclinical model of MASH as well as in liver biopsies of patients with obesity undergoing bariatric surgery. Our findings reveal that expression of ODC1 and the levels of putrescine, but not spermidine nor spermine, are elevated in hepatic tissue of both diet-induced MASH mice and patients with biopsy-proven MASH compared with control mice and patients without MASH, respectively. Furthermore, we found that the levels of putrescine were positively associated with higher aspartate aminotransferase concentrations in serum and an increased SAF score (steatosis, activity, fibrosis). Additionally, in in vitro assays using human HepG2 cells, we demonstrate that elevated levels of putrescine exacerbate the cellular response to palmitic acid, leading to decreased cell viability and increased release of CK-18. Our results support an association between the expression of ODC1 and the progression of MASLD, which could have translational relevance in understanding the onset of this disease. © 2024 The Pathological Society of Great Britain and Ireland.

Keywords: liver metabolism; metabolic dysfunction‐associated steatohepatitis; metabolic dysfunction‐associated steatotic liver disease; obesity; ornithine decarboxylase; polyamine

DOI: https://doi.org/10.1002/path.6330

Heliyon. 2024 Jul 15. 10(13): e33838

Analysis of the effect of hypusination in myeloid cells on colitis and colitis-associated cancer.

Alain P Gobert, Jordan Finley, Mohammad Asim, Daniel P Barry, Margaret M Allaman, Caroline V Hawkins, Kamery J Williams, Alberto G Delagado, Raghavendra G Mirmira, Shilin Zhao, M Blanca Piazuelo, M Kay Washington, Lori A Coburn, Keith T Wilson.

Hypusine is an amino acid synthesized by the enzyme deoxyhypusine synthase (DHPS). It is critical for the activity of eukaryotic translation initiation factor 5A (EIF5A). We reported that hypusination i) in macrophages supports the innate response towards pathogenic bacteria and ii) in epithelial cells maintains intestinal homeostasis. Herein, we investigated the effect of myeloid hypusination on the outcome of colitis and colitis-associated cancer. We found that patients with Crohn's disease exhibit increased levels of DHPS and EIF5AHyp in cells infiltrating the colon lamina propria. However, the specific deletion of Dhps in myeloid cells had no impact on clinical, histological, or inflammatory parameters in mice treated with dextran sulfate sodium (DSS). Further, tumorigenesis and level of dysplasia were not affected by myeloid deletion of Dhps in the azoxymethane-DSS model. The composition of the fecal and the mucosa-associated microbiome was similar in animals lacking or not DHPS in myeloid cells. Thus, hypusination in myeloid cells does not regulate colitis associated with epithelial injury and colitis-associated cancer. Enhancement of the DHPS/hypusine pathway in patients with inflammatory bowel disease could have therapeutic impact through epithelial effects, but modulation of hypusination in myeloid cells will be unlikely to affect the disease.

Keywords: Colon; Colorectal cancer; Gut microbiota; Hypusine; Inflammation; Inflammatory bowel diseases

DOI: https://doi.org/10.1016/j.heliyon.2024.e33838

Clin Res Hepatol Gastroenterol. 2024 Jul 16. pii: S2210-7401(24)00142-6. [Epub ahead of print]48(7): 102421

Spermine oxidase regulates liver inflammation and fibrosis through β-catenin pathway.

Tingting Hu, Wenqing Tang, Wandong Hong, Qingke Huang, Xuecheng Sun, Wenzhi Wu, Jie Zhang.

BACKGROUND: Spermine oxidase (SMOX), an inducible enzyme involved in the catabolic pathway of polyamine, was found to be upregulated in hepatocellular carcinoma and might be an important oncogene of it in our previous studies. This study attempted to further investigate its relationship with liver inflammation and fibrosis both in vitro and in vivo.METHODS: The effect of SMOX inhibition on LPS-induced inflammatory response in mouse liver cell line AML12 was validated by using small interfering RNA or SMOX inhibitor MDL72527. Western blotting and immunofluorescence were utilized to verify whether LPS could induce β-catenin to transfer into the nucleus and whether it could be reversed by interfering with the expression of SMOX or using SMOX inhibitor. Then, the SMOX inhibitor MDL72527 and SMOX knockout mice were used to verify the hypothesis above in vivo.
RESULTS: The expression of SMOX could be induced by LPS in AML12 cells. The inhibition of SMOX could inhibit LPS-induced inflammatory response in AML12 cells. LPS could induce β-catenin transfer from cytoplasm to nucleus, while SMOX downregulation or inhibition could partially reverse this process. In vivo intervention with SMOX inhibitor MDL72527 or SMOX knockout mice could significantly improve the damage of liver function, reduce intrahepatic inflammation, inhibit the nuclear transfer of β-catenin in liver tissue, and alleviate carbon tetrachloride-induced liver fibrosis in mice.
CONCLUSION: SMOX can promote the inflammatory response and fibrosis of hepatocytes. It provides a new therapeutic strategy for hepatitis and liver fibrosis, inhibiting early liver cancer.

Keywords: Inflammation; Lipopolysaccharide; Liver cirrhosis; Spermine oxidase

DOI: https://doi.org/10.1016/j.clinre.2024.102421

Am J Cancer Res. 2024 ;14(6): 2805-2822

Extracellular putrescine can augment the epithelial-mesenchymal transition of gastric cancer cells by promoting MAL2 expression by elevating H3K27ac in its promoter region.

Chenxiao Bi, Chengyu Li, Liangxiu Xing, Zixuan Lu, Haiyan Liu, Tao Hu, Bin Wang, Chengxia Liu.

Dysregulation of polyamine metabolism has been associated with the development of many cancers. However, little information has been reported about the associations between elevated extracellular putrescine and epithelial-mesenchymal transition (EMT) of gastric cancer (GC) cells. In this study, the influence of extracellular putrescine on the malignant behavior and EMT of the AGS and MKN-28 cells was investigated, followed by RNA sequencing profiling of transcriptomic alterations and CUT&Tag sequencing capturing H3K27ac variations across the global genome using extracellular putrescine. Our results demonstrated that the administration of extracellular putrescine significantly promoted the proliferation, migration, invasion, and expression of N-cadherin in GC cells. We also observed elevated H3K27ac in MKN-28 cells but not in AGS cells when extracellular putrescine was used. A combination of transcriptomic alterations and genome-wide variations of H3K27ac highlighted the upregulated MAL2 and H3K27ac in its promoter region. Knockdown and overexpression of MAL2 were found to inhibit and promote EMT, respectively, in AGS and MKN-28 cells. We demonstrated that extracellular putrescine could upregulate MAL2 expression by elevating H3K27ac in its promoter region, thus triggering augmented EMT in GC cells.

Keywords: CUT&Tag; H3K27ac; MAL2; Putrescine; gastric cancer

DOI: https://doi.org/10.62347/BEUV4081

NPJ Parkinsons Dis. 2024 Jul 20. 10(1): 133

Adult-onset deletion of ATP13A2 in mice induces progressive nigrostriatal pathway dopaminergic degeneration and lysosomal abnormalities.

Madalynn L Erb, Kayla Sipple, Nathan Levine, Xi Chen, Darren J Moore.

Although most cases of Parkinson's disease (PD) are sporadic, mutations in over 20 genes are known to cause heritable forms of the disease. Recessive loss-of-function mutations in ATP13A2, a lysosomal transmembrane P5B-type ATPase and polyamine exporter, can cause early-onset familial PD. Familial ATP13A2 mutations are also linked to related neurodegenerative diseases, including Kufor-Rakeb syndrome, hereditary spastic paraplegias, neuronal ceroid lipofuscinosis, and amyotrophic lateral sclerosis. Despite the severe effects of ATP13A2 mutations in humans, ATP13A2 knockout (KO) mice fail to exhibit neurodegeneration even at advanced ages, making it challenging to study the neuropathological effects of ATP13A2 loss in vivo. Germline deletion of ATP13A2 in rodents may trigger the upregulation of compensatory pathways during embryonic development that mask the full neurotoxic effects of ATP13A2 loss in the brain. To explore this idea, we selectively deleted ATP13A2 in the adult mouse brain by the unilateral delivery of an AAV-Cre vector into the substantia nigra of young adult mice carrying conditional loxP-flanked ATP13A2 KO alleles. We observe a progressive loss of striatal dopaminergic nerve terminals at 3 and 10 months after AAV-Cre delivery. Cre-injected mice also exhibit robust dopaminergic neuronal degeneration in the substantia nigra at 10 months. Adult-onset ATP13A2 KO also recreates many of the phenotypes observed in aged germline ATP13A2 KO mice, including lysosomal abnormalities, p62-positive inclusions, and neuroinflammation. Our study demonstrates that the adult-onset homozygous deletion of ATP13A2 in the nigrostriatal pathway produces robust and progressive dopaminergic neurodegeneration that serves as a useful in vivo model of ATP13A2-related neurodegenerative diseases.

DOI: https://doi.org/10.1038/s41531-024-00748-5