The Warburg Effect Dictates the Mechanism of Butyrate Mediated Histone Acetylation and Cell Proliferation

By Dallas R. Donohoe, L. Collins, A. Wali, R. Bigler, Wei Sun, S. Bultman. Molecules and Cells, 2012

868 citations recorded by the source corpus.

SUMMARY Widespread changes in gene expression drive tumorigenesis, yet our knowledge of how aberrant epigenomic and transcriptome profiles arise in cancer cells is poorly understood. Here, we demonstrate that metabolic transformation plays an important role. Butyrate is the primary energy source of normal colonocytes and is metabolized to acetyl-CoA, which was shown to be important not only for energetics but also for HAT activity. Due to the Warburg effect, cancerous colonocytes rely on glucose as their primary energy source so butyrate accumulated and functioned as an HDAC inhibitor. Although both mechanisms increased histone acetylation, different target genes were upregulated. Consequently, butyrate stimulated the proliferation of normal colonocytes and cancerous colonocytes when the Warburg effect was prevented from occurring, whereas it inhibited the proliferation of cancerous colonocytes undergoing the Warburg effect. These findings link a common metabolite to epigenetic mechanisms that are differentially utilized by normal and cancerous cells because of their inherent metabolic differences.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/b9fdfe15e8258e5763d98115e2a0c0862d890445

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

In Molecular Biology

Citations in the corpus

Fat, Fiber and Cancer Risk in African Americans and Rural Africans (2015, neutral): “Second, it has a remarkably wide variety of antineoplastic properties, best exemplified by its function as a histone deacetylase inhibitor 52 , its capacity to down-regulate the key canonical W nt-signaling pathway linked to colonic carcinogenesis 53 , and its ability to reduce the burden of…”
Butyrate: A Double-Edged Sword for Health? (2018, background): “Many of the anticancer activities of butyrate have been found to be mediated through HDAC inhibition, which includes inhibition of cell proliferation, induction of cell differentiation or apoptosis, and induction or repression of gene expression (56, 57).”
Crosstalk between Microbiota-Derived Short-Chain Fatty Acids and Intestinal Epithelial HIF Augments Tissue Barrier Function (2015, neutral): “, the Warburg effect) and that, in high concentrations of butyrate, functions primarily as an HDAC inhibitor (Donohoe et al., 2012).”
Acetyl coenzyme A: a central metabolite and second messenger. (2015, background): “…2015; Takahashi et al., 2006), but also for the preferential transactivation of genes involved in cell growth and replication (Cai et al., 2011; Donohoe et al., 2012; Lee et al., 2014; Shi and Tu, 2013), glycolysis (Wellen et al., 2009), and resistance to oxidative stress (Shimazu et al.,…”
Microbiota in health and diseases (2022, background): “In colon cancer cells, butyrate is metabolized to a lesser extent compared to normal cells, thereby accumulating as HDAC inhibitor to inhibit cell proliferation and induce cell apoptosis.(346) The difference observed in this study may lay between host genetic background, the age, and the presence of”
Understanding the Holobiont: How microbial metabolites affect human health and shape the immune system (2017, background): “Arpaia et al., 2013; Brown et al., 2003; Chang et al., 2014; Donohoe et al., 2012; Kalina et al., 2002; Kim et al., 2016; Le Poul et al., 2003; Macia et al., 2015; Maslowski et al., 2009; Millard et al., 2002; Nilsson et al., 2003; Singh et al., 2010; Smith et al., 2013; Thangaraju et al., 2009a,…”
Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism (2016, background): “Butyrate appears to have a dual role, sometimes referred to as the “butyrate paradox” whereby it induces proliferation in healthy colonocytes but terminal differentiation and apoptosis in transformed cells.(33,34)”
The role of short-chain fatty acids in the interplay between gut microbiota and diet in cardio-metabolic health (2021, background): “This dual role is known as the “butyrate paradox” or “Warburg effect”.(101,114) Additionally, intestinal epithelial cells (IEC) are connected by transmembrane proteins, namely, tight-junctions, adherent junctions, and desmosomes.”