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Histone acetyltransferase promotes fluoride toxicity in LS8 cells.
Huidan Deng1, Natsumi Fujiwara2, Hengmin Cui1
1College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu, Sichuan, 611130, China.
Chemosphere
|January 14, 2020
Summary
Fluoride activates histone acetyltransferases (HATs) to acetylate p53, leading to cell growth inhibition and DNA damage in LS8 cells. Inhibiting HATs mitigates fluoride-induced toxicity, suggesting HAT modulation as a therapeutic target.
Area of Science:
- Biochemistry
- Cell Biology
- Toxicology
Background:
- Fluoride exposure is known to increase acetylated-p53 (Ac-p53) in LS8 cells and rodent ameloblasts.
- The precise molecular mechanisms by which fluoride induces p53 acetylation and the upstream pathways involved remain incompletely understood.
Purpose of the Study:
- To investigate the role of histone acetyltransferases (HATs) in fluoride-induced p53 acetylation.
- To elucidate the upstream molecular pathways affected by fluoride in LS8 cells.
- To evaluate the potential of HAT inhibition as a therapeutic strategy against fluoride toxicity.
Main Methods:
- Western blotting to analyze HAT protein levels and post-translational modifications.
- Co-immunoprecipitation (co-IP) to assess p53-HAT binding.
- MTT assays to measure cell growth inhibition.
- Treatment with specific HAT inhibitors (MG149 and Anacardic Acid) prior to fluoride exposure.
Main Results:
- Fluoride activates HATs (CBP, p300, PCAF, Tip60) leading to increased p53 acetylation.
- NaF treatment enhanced p53 binding with CBP and PCAF.
- Fluoride increased active forms of p300, CBP, and phospho-Tip60.
- HAT inhibitors MG149 and Anacardic Acid reversed fluoride-induced cell growth inhibition.
- Inhibitor treatment reduced fluoride-induced p53 acetylation, caspase-3 cleavage, γH2AX expression, and cytochrome-c release.
Conclusions:
- Fluoride-induced p53 acetylation by HATs contributes to cell growth inhibition, apoptosis, DNA damage, and mitochondrial damage in LS8 cells.
- Modulation of HAT activity presents a potential therapeutic target for mitigating fluoride toxicity in ameloblasts.
