The Aneugenicity of Ketone Bodies in Colon Epithelial Cells Is Mediated by Microtubule Hyperacetylation and Is Blocked by Resveratrol

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,...

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Main Authors: Haruka Sudo, Akira Kubo
Format: Article
Language:English
Published: MDPI AG 2021-08-01
Series:International Journal of Molecular Sciences
Subjects:
Online Access:https://www.mdpi.com/1422-0067/22/17/9397
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author Haruka Sudo
Akira Kubo
author_facet Haruka Sudo
Akira Kubo
author_sort Haruka Sudo
collection DOAJ
description 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.
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spelling doaj.art-35053f22da9c4ab7b4008c3baec8d4e72023-11-22T10:42:46ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-08-012217939710.3390/ijms22179397The Aneugenicity of Ketone Bodies in Colon Epithelial Cells Is Mediated by Microtubule Hyperacetylation and Is Blocked by ResveratrolHaruka Sudo0Akira Kubo1Faculty of Health Science, Tokoha University, 1-30, Mizuochi-cho, Aoi-ku, Shizuoka-shi, Shizuoka 420-0831, JapanFaculty of Health Science, Tokoha University, 1-30, Mizuochi-cho, Aoi-ku, Shizuoka-shi, Shizuoka 420-0831, JapanDiabetes 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.https://www.mdpi.com/1422-0067/22/17/9397colon canceraneuploidymicrotubule severingdiabetes
spellingShingle Haruka Sudo
Akira Kubo
The Aneugenicity of Ketone Bodies in Colon Epithelial Cells Is Mediated by Microtubule Hyperacetylation and Is Blocked by Resveratrol
International Journal of Molecular Sciences
colon cancer
aneuploidy
microtubule severing
diabetes
title The Aneugenicity of Ketone Bodies in Colon Epithelial Cells Is Mediated by Microtubule Hyperacetylation and Is Blocked by Resveratrol
title_full The Aneugenicity of Ketone Bodies in Colon Epithelial Cells Is Mediated by Microtubule Hyperacetylation and Is Blocked by Resveratrol
title_fullStr The Aneugenicity of Ketone Bodies in Colon Epithelial Cells Is Mediated by Microtubule Hyperacetylation and Is Blocked by Resveratrol
title_full_unstemmed The Aneugenicity of Ketone Bodies in Colon Epithelial Cells Is Mediated by Microtubule Hyperacetylation and Is Blocked by Resveratrol
title_short The Aneugenicity of Ketone Bodies in Colon Epithelial Cells Is Mediated by Microtubule Hyperacetylation and Is Blocked by Resveratrol
title_sort aneugenicity of ketone bodies in colon epithelial cells is mediated by microtubule hyperacetylation and is blocked by resveratrol
topic colon cancer
aneuploidy
microtubule severing
diabetes
url https://www.mdpi.com/1422-0067/22/17/9397
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