p53 β-hydroxybutyrylation attenuates p53 activity

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• p53 is a critical tumor suppressor protein.
• Posttranslational modifications regulate p53 activity.
• Beta-hydroxybutyrylation (Kbhb) is a newly identified histone modification.

Purpose of the Study:

• To investigate if p53 is subject to beta-hydroxybutyrylation (Kbhb).
• To determine the functional consequences of p53 Kbhb on p53 activity and downstream gene expression.
• To explore the role of p53 Kbhb in cancer and its potential as a therapeutic target.

Main Methods:

• Western blotting to detect p53 modification.
• Cell culture experiments with BHB treatment.
• Analysis of p53 downstream gene expression (p21, PUMA).
• In vivo studies using fasted mice and gamma-irradiation.

Main Results:

• p53 is modified by Kbhb at specific lysine residues (120, 319, 370).
• p53 Kbhb levels increase upon BHB treatment and during fasting in vivo.
• CBP was identified as the enzyme catalyzing p53 Kbhb.
• p53 Kbhb reduces p53 acetylation, leading to decreased p21 and PUMA expression.
• Reduced cell growth arrest and apoptosis were observed under p53-activating conditions.

Conclusions:

• BHB-mediated p53 Kbhb is a novel regulatory mechanism for p53 activity.
• This modification links ketone bodies to tumor biology.
• p53 Kbhb represents a potential therapeutic target for cancer treatment.