p53 β-hydroxybutyrylation attenuates p53 activity

p53 is an essential tumor suppressor, whose activity is finely tuned by the posttranslational modifications. Previous research has reported that β-hydroxybutyrate (BHB) induces β-hydroxybutyrylation (Kbhb), which is a novel histone posttranslational modification. Here we report that p53 is modified...

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Bibliographic Details
Published in:Cell death & disease 2019-03, Vol.10 (3), p.243, Article 243
Main Authors: Liu, Kun, Li, Fangzhou, Sun, Qianqian, Lin, Ning, Han, Haichao, You, Kaiqiang, Tian, Feng, Mao, Zebin, Li, Tingting, Tong, Tanjun, Geng, Meiyu, Zhao, Yingming, Gu, Wei, Zhao, Wenhui
Format: Article
Language:English
Subjects:
3-Hydroxybutyric Acid - blood
3-Hydroxybutyric Acid - metabolism
3-Hydroxybutyric Acid - pharmacology
Acetylation
Animals
Apoptosis
Apoptosis - drug effects
Apoptosis - genetics
Apoptosis Regulatory Proteins - genetics
Apoptosis Regulatory Proteins - metabolism
Cancer
Chromatography, Liquid
Cyclin-Dependent Kinase Inhibitor p21 - genetics
Cyclin-Dependent Kinase Inhibitor p21 - metabolism
DNA Damage - drug effects
DNA Damage - genetics
Genotoxicity
HEK293 Cells
Humans
Ketones
Lysine - metabolism
Male
Mice
Mice, Inbred C57BL
p53 Protein
Peptide Fragments - genetics
Peptide Fragments - metabolism
Protein Processing, Post-Translational
Radiation
Sialoglycoproteins - genetics
Sialoglycoproteins - metabolism
Tandem Mass Spectrometry
Therapeutic applications
Thymus
Thymus Gland - metabolism
Thymus Gland - radiation effects
Tumor suppressor genes
Tumor Suppressor Protein p53 - antagonists & inhibitors
Tumor Suppressor Protein p53 - chemistry
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
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Summary:p53 is an essential tumor suppressor, whose activity is finely tuned by the posttranslational modifications. Previous research has reported that β-hydroxybutyrate (BHB) induces β-hydroxybutyrylation (Kbhb), which is a novel histone posttranslational modification. Here we report that p53 is modified by kbhb and that this modification occurs at lysines 120, 319, and 370 of p53. We demonstrate that the level of p53 kbhb is dramatically increased in cultured cells treated with BHB and in thymus tissues of fasted mice, and that CBP catalyze p53 kbhb. We show that p53 kbhb results in lower levels of p53 acetylation and reduced expression of the p53 downstream genes p21 and PUMA, as well as reduced cell growth arrest and apoptosis in cultured cells under p53-activating conditions. Similar results were observed in mouse thymus tissue under starvation conditions, which result in increased concentrations of serum BHB, and in response to genotoxic stress caused by γ-irradiation to activate p53. Our findings thus show that BHB-mediated p53 kbhb is a novel mechanism of p53 activity regulation, which may explain the link between ketone bodies and tumor, and which may provide promising therapeutic target for cancer treatment.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-019-1463-y