CACUL1 reciprocally regulates SIRT1 and LSD1 to repress PPARγ and inhibit adipogenesis
Autor: | Eun-Joo Kim, Min Jun Jang, Jeong Woo Kim, Soo-Jong Um, Ui-Hyun Park, Hanbyeul Choi |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Cancer Research Immunology Article Epigenesis Genetic Histones Mice 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound 0302 clinical medicine Sirtuin 1 3T3-L1 Cells Adipocyte Stilbenes Adipocytes Animals Humans Epigenetics lcsh:QH573-671 Receptor Histone Demethylases Adipogenesis biology Sequence Analysis RNA lcsh:Cytology Chemistry Cell Differentiation Promoter Cell Biology Cullin Proteins HCT116 Cells Cell biology PPAR gamma Gene expression profiling HEK293 Cells 030104 developmental biology Histone Nuclear receptor Resveratrol 030220 oncology & carcinogenesis biology.protein lipids (amino acids peptides and proteins) Carrier Proteins Co-Repressor Proteins Signal Transduction |
Zdroj: | CELL DEATH & DISEASE(8) Cell Death and Disease, Vol 8, Iss 12, Pp 1-14 (2017) Cell Death & Disease |
ISSN: | 2041-4889 |
DOI: | 10.1038/s41419-017-0070-z |
Popis: | Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differentiation and is closely linked to the development of obesity. Despite great progress in elucidating the transcriptional network of PPARγ, epigenetic regulation of this pathway by histone modification remains elusive. Here, we found that CDK2-associated cullin 1 (CACUL1), identified as a novel SIRT1 interacting protein, directly bound to PPARγ through the co-repressor nuclear receptor (CoRNR) box 2 and repressed the transcriptional activity and adipogenic potential of PPARγ. Upon CACUL1 depletion, less SIRT1 and more LSD1 were recruited to the PPARγ-responsive gene promoter, leading to increased histone H3K9 acetylation, decreased H3K9 methylation, and PPARγ activation during adipogenesis in 3T3-L1 cells. These findings were reversed upon fasting or resveratrol treatment. Further, gene expression profiling using RNA sequencing supported the repressive role of CACUL1 in PPARγ activation and fat accumulation. Finally, we confirmed CACUL1 function in human adipose-derived stem cells. Overall, our data suggest that CACUL1 tightly regulates PPARγ signaling through the mutual opposition between SIRT1 and LSD1, providing insight into its potential use for anti-obesity treatment. |
Databáze: | OpenAIRE |
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