Research Papers:

Butyrate decreases its own oxidation in colorectal cancer cells through inhibition of histone deacetylases

Anna Han, Natalie Bennett, Bettaieb Ahmed, Jay Whelan and Dallas R. Donohoe _

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Oncotarget. 2018; 9:27280-27292. https://doi.org/10.18632/oncotarget.25546

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Anna Han1, Natalie Bennett1, Bettaieb Ahmed1, Jay Whelan1 and Dallas R. Donohoe1

1Department of Nutrition, University of Tennessee, Knoxville, TN 37996, USA

Correspondence to:

Dallas R. Donohoe, email: [email protected]

Keywords: butyrate; HDAC inhibitor; SCAD; β-oxidation; metaboloepigenetics

Received: July 20, 2017    Accepted: May 14, 2018    Published: June 05, 2018


Colorectal cancer is characterized by an increase in the utilization of glucose and a diminishment in the oxidation of butyrate, which is a short chain fatty acid. In colorectal cancer cells, butyrate inhibits histone deacetylases to increase the expression of genes that slow the cell cycle and induce apoptosis. Understanding the mechanisms that contribute to the metabolic shift away from butyrate oxidation in cancer cells is important in in understanding the beneficial effects of the molecule toward colorectal cancer. Here, we demonstrate that butyrate decreased its own oxidation in cancerous colonocytes. Butyrate lowered the expression of short chain acyl-CoA dehydrogenase, an enzyme that mediates the oxidation of short-chain fatty acids. Butyrate does not alter short chain acyl-CoA dehydrogenase levels in non-cancerous colonocytes. Trichostatin A, a structurally unrelated inhibitor of histone deacetylases, and propionate also decreased the level of short chain acyl-CoA dehydrogenase, which alluded to inhibition of histone deacetylases as a part of the mechanism. Knockdown of histone deacetylase isoform 1, but not isoform 2 or 3, inhibited the ability of butyrate to decrease short chain acyl-CoA dehydrogenase expression. This work identifies a mechanism by which butyrate selective targets colorectal cancer cells to reduce its own metabolism.

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