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Spermidine/spermine-N(1)-acetyltransferase (SSAT) was identified as a crucial enzyme regulating cellular polyamine content, impacting normal and neoplastic growth, ion channel regulation, and potentially cancer chemotherapy. SSAT activity was highly regulated and could be induced by various stimuli, affecting polyamine homeostasis and linking polyamine metabolism to lipid and carbohydrate metabolism. Increased SSAT activity led to a futile cycle consuming ATP and acetyl-CoA, and was associated with adverse effects such as pancreatic cell death, tissue growth blockage, behavioral changes, and hair loss. SSAT also interacted with proteins like hypoxia-inducible factor-1 alpha and NF-kappaB, though the exact mechanisms were unclear. While SSAT was considered a potential target for diseases beyond cancer, its broad physiological effects necessitated careful targeting to avoid toxicity.

The study created transgenic mice overexpressing the SSAT gene, leading to significant changes in polyamine levels and permanent hair loss, with the liver showing a notable reduction in spermine. Despite high SSAT mRNA levels, enzyme activity increased only moderately unless induced by ZnSO4 or DENSPM, which drastically boosted enzyme activity and depleted liver polyamines, resulting in high mortality and liver damage. This indicated that SSAT overexpression made the mice highly sensitive to polyamine analogues and suggested a post-transcriptional regulation mechanism for SSAT expression involving translational or RNA processing control.

The study involved generating a transgenic mouse line overexpressing the SSAT gene under a mouse metallothionein I promoter, leading to significant changes in tissue polyamine pools and delayed permanent hair loss compared to previous models. The liver was notably affected, with drastic reductions in spermine and increases in putrescine. Despite high levels of SSAT mRNA, enzyme activity was only moderately elevated unless induced by ZnSO4 or the polyamine analogue DENSPM, which caused a massive increase in enzyme activity and depletion of spermidine and spermine pools. This treatment led to high mortality and liver damage, indicating that SSAT overexpression made the mice highly sensitive to polyamine analogues, suggesting a post-transcriptional regulation mechanism.

The study explored how altering the expression of spermidine/spermine N1-acetyltransferase (SSAT) affected fat metabolism in mice. Transgenic mice overexpressing SSAT showed increased metabolic activity through the polyamine pathway, resulting in a leaner phenotype with reduced white adipose acetyl- and malonyl-CoA pools and enhanced glucose and palmitate oxidation. In contrast, SSAT knockout mice had decreased metabolic flux, increased body fat, and lower oxidation rates, especially on a high-fat diet. These results indicated that SSAT expression influenced acetyl- and malonyl-CoA levels, affecting fatty acid biosynthesis and oxidation, and thus body fat accumulation. The study underscored the role of SSAT in polyamine metabolism and its impact on fat metabolism via acetyl-CoA modulation.

The study explored the impact of overexpressing the enzyme spermidine/spermine N1-acetyltransferase (SSAT) in TRAMP mice, a model for prostate cancer. By cross-breeding these mice with SSAT-overexpressing mice, researchers observed a significant reduction in tumor growth, with genitourinary tract weights being 4 to 12 times less than in TRAMP mice alone by 30 to 36 weeks of age. This tumor suppression was attributed to increased polyamine catabolism, which depleted acetyl-CoA and S-adenosylmethionine, despite increased polyamine biosynthesis. Histopathological analysis showed less advanced tumors in TRAMP/SSAT mice, suggesting that SSAT overexpression could be a promising therapeutic strategy for prostate cancer. Additionally, a genitourinary disease index was developed to assess the treatment's impact, particularly in the C57BL/6 mouse background.

The study used transgenic mice with targeted expression of spermidine/spermine N1-acetyltransferase (SSAT) in hair follicle keratinocytes to investigate susceptibility to skin cancer. These K6-SSAT transgenic mice, bred onto a tumor-resistant C57BL/6 background, showed a 10-fold increase in epidermal tumors when exposed to a carcinogenesis protocol involving 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate. The transgenic mice exhibited elevated SSAT activity and protein levels, along with increased putrescine and N1-acetylspermidine, indicating enhanced polyamine catabolism. The study concluded that this activation of polyamine catabolism might play a crucial role in chemically induced skin cancer, as evidenced by the early onset and progression to carcinomas in the transgenic mice.

In this study, overexpression of spermidine/spermine N1-acetyltransferase (SSAT) in transgenic mice led to increased putrescine levels, causing permanent hair loss and skin abnormalities such as dermal cysts and epidermal utriculi due to disturbed keratinocyte differentiation. This was characterized by altered expression of cytokeratins and filaggrin. The study found that reducing putrescine levels with DFMO treatment could alleviate these skin changes and promote hair regrowth, highlighting the importance of proper polyamine metabolism regulation for normal keratinocyte differentiation and hair follicle function. These findings had potential implications for understanding skin disorders and hair growth.