Journal Article

p53 β-hydroxybutyrylation attenuates p53 activity

Geng, Meiyu, Gu, Wei, Han, Haichao, Zhao, Yingming, Tian, Feng, Tong, Tanjun, Lin, Ning, You, Kaiqiang, Liu, Kun, Li, Tingting, Mao, Zebin, Li, Fangzhou, Zhao, Wenhui, Sun, Qianqian

2019

Overview

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.

• Publisher: Nature Publishing Group UK,Springer Nature B.V
• Subject: 3-Hydroxybutyric Acid - blood / 3-Hydroxybutyric Acid - metabolism / 3-Hydroxybutyric Acid - pharmacology / 42 / 42/109 / 42/70 / 42/89 / 631/337/458/1275 / 631/67/1244 / 82 / 82/1 / 82/29 / 82/58 / 82/80 / 82/83 / Acetylation / Animals / Antibodies / Apoptosis / Apoptosis - drug effects / Apoptosis - genetics / Apoptosis Regulatory Proteins - genetics / Apoptosis Regulatory Proteins - metabolism / Biochemistry / Biomedical and Life Sciences / Cancer / Cell Biology / Cell Culture / 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 / Immunology / Ketones / Life Sciences / 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