Abstract
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.
Highlights
Colorectal cancer (CRC) is the third most common and lethal cancer in the United States [1]
RNAi knockdown of HDAC2 and HDAC3 in HCT116 cells did not impact Short chain acyl-CoA dehydrogenase (SCAD) levels like as histone deacetylase 1 (HDAC1) (Supplementary Figure 4). These findings demonstrate that butyrate targets HDAC1 to decrease SCAD levels in the colorectal cancer cells
Normal colonocytes prefer to oxidize butyrate as a primary energy source whereas cancerous colonocytes increase glucose utilization
Summary
Colorectal cancer (CRC) is the third most common and lethal cancer in the United States [1]. Diet is one of the strongest influential risk factors in the development of colorectal cancer. Dietary intervention has been suggested to be an effective way to decrease colorectal cancer development and mortality [2,3,4]. The fermentation of dietary fiber in the proximal colon produces bacterial derived-short chain fatty acids (SCFAs), which include acetate, propionate and butyrate. Among these SCFAs, butyrate has been considered a critical metabolite that mediates the tumor repressive effect of dietary fiber toward colorectal cancer [9,10,11]
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