RRC ID 68912
Author Sudo H, Kubo A.
Title The Aneugenicity of Ketone Bodies in Colon Epithelial Cells Is Mediated by Microtubule Hyperacetylation and Is Blocked by Resveratrol.
Journal Int J Mol Sci
Abstract Diabetes mellitus (DM) is considered to be associated with an increased risk of colorectal cancer. Recent studies have also revealed that tubulin hyperacetylation is caused by a diabetic status and we have reported previously that, under microtubule hyperacetylation, a microtubule severing protein, katanin-like (KL) 1, is upregulated and contributes to tumorigenesis. To further explore this phenomenon, we tested the effects of the ketone bodies, acetoacetate and β-hydroxybutyrate, in colon and fibroblast cells. Both induced microtubule hyperacetylation that responded differently to a histone deacetylase 3 knockdown. These two ketone bodies also generated intracellular reactive oxygen species (ROS) and hyperacetylation was commonly inhibited by ROS inhibitors. In a human fibroblast-based microtubule sensitivity test, only the KL1 human katanin family member showed activation by both ketone bodies. In primary cultured colon epithelial cells, these ketone bodies reduced the tau protein level and induced KL1- and α-tubulin acetyltransferase 1 (ATAT1)-dependent micronucleation. Resveratrol, known for its tumor preventive and tubulin deacetylation effects, inhibited this micronucleation. Our current data thus suggest that the microtubule hyperacetylation induced by ketone bodies may be a causal factor linking DM to colorectal carcinogenesis and may also represent an adverse effect of them that needs to be controlled if they are used as therapeutics.
Volume 22(17)
Published 2021-8-30
DOI 10.3390/ijms22179397
PII ijms22179397
PMID 34502304
PMC PMC8430621
MeSH Acetylation Aneugens / pharmacology* Animals Antioxidants / pharmacology Cells, Cultured Colon / drug effects* Colon / metabolism Colonic Neoplasms / drug therapy Colonic Neoplasms / metabolism Colonic Neoplasms / pathology* Epithelial Cells / drug effects Epithelial Cells / metabolism Fibroblasts / drug effects Fibroblasts / metabolism Humans Ketone Bodies / pharmacology* Microtubules / drug effects* Microtubules / metabolism Rats Resveratrol / pharmacology*
IF 4.556
Human and Animal Cells HCT116(RCB2979)