• BMB Reports
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• v.49 no.8
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• pp.401-402
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• 2016

S6K1 is a key regulator of cell growth, cell size, and metabolism. Although the role of cytosolic S6K1 in cellular processes is well established, the function of S6K1 in the nucleus remains poorly understood. Our recent study has revealed that S6K1 is translocated into the nucleus upon adipogenic stimulus where it directly binds to and phosphorylates H2B at serine 36. Such phosphorylation promotes EZH2 recruitment and subsequent histone H3K27 trimethylation on the promoter of its target genes including Wnt6, Wnt10a, and Wnt10b, leading to repression of their expression. S6K1-mediated suppression of Wnt genes facilitates adipogenic differentiation through the expression of adipogenic transcription factors PPARγ and Cebpa. White adipose tissues from S6K1-deficient mice consistently exhibit marked reduction in H2BS36 phosphorylation (H2BS36p) and H3K27 trimethylation (H3K27me3), leading to enhanced expression of Wnt genes. In addition, expression levels of H2BS36p and H3K27me3 are highly elevated in white adipose tissues from mice fed on high-fat diet or from obese humans. These findings describe a novel role of S6K1 as a transcriptional regulator controlling an epigenetic network initiated by phosphorylation of H2B and trimethylation of H3, thus shutting off Wnt gene expression in early adipogenesis.

• Journal of Ginseng Research
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• v.44 no.1
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• pp.58-66
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• 2020

Background: The biological and pharmacological effects of BST204, a fermented ginseng extract, have been reported in various disease conditions. However, its molecular action in metabolic disease remains poorly understood. In this study, we identified the antiadipogenic activity of BST204 resulting from its inhibition of the S6 kinase 1 (S6K1) signaling pathway. Methods: The inhibitory effects of BST204 on S6K1 signaling were investigated by immunoblot, nuclear fractionation, immunoprecipitation analyses. The antiadipogenic effect of BST204 was evaluated by measuring mRNA levels of adipogenic genes and by chromatin immunoprecipitation and quantitative real-time polymerase chain reaction analysis. Results: Treatment with BST204 inhibited activation and nuclear translocation of S6K1, further decreasing the interaction between S6K1 and histone H2B in 10T1/2 mesenchymal stem cells. Subsequently, phosphorylation of H2B at serine 36 (H2BS36p) by S6K1 was reduced by BST204, inducing an increase in the mRNA expression of Wnt6, Wnt10a, and Wnt10b, which disturbed adipogenic differentiation and promoted myogenic and early osteogenic gene expression. Consistently, BST204 treatment during adipogenic commitment suppressed the expression of adipogenic marker genes and lipid drop formation. Conclusion: Our results indicate that BST204 blocks adipogenesis of mesenchymal stem cells through the inhibition of S6K1-mediated histone phosphorylation. This study suggests the potential therapeutic strategy using BST204 to combat obesity and musculoskeletal diseases.