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.
Highlights
Diabetes mellitus (DM) has been associated with increased risk of multiple cancer types, including colorectal cancer (CRC) [1,2]
We have reported that microtubule hyperacetylation induces aneuploidy via enhanced katanin-like1 microtubule severing [18]
We studied the expression levels of enzymes associated with α-tubulin lysine 40 acetylation (α-tubulin acetyltransferase 1 (ATAT1) [25,26]) or deacetylation (histone deacetylase 6 (HDAC6) [27], sirtuin 2 (SIRT2) [28], and HDAC3 [29])
Summary
Diabetes mellitus (DM) has been associated with increased risk of multiple cancer types, including colorectal cancer (CRC) [1,2]. Common risk factors such as obesity, physical inactivity, and smoking are likely to contribute to this increased CRC risk in DM patients. This CRC association with DM has been reported to be maintained when these factors are adjusted [3], indicating that diabetes itself includes tumor promoting mechanisms in its pathology. A recent report has indicated that the local synthesis of ketone bodies by 3-hydroxy-3-methylglutaryl-CoA synthetase 2 (HMGCS2) maintains intestinal stem cell homeostasis via the activation of
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