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

Donohoe, Dallas R.; Collins, Leonard B.; Wali, Aminah; Bigler, Rebecca L.; Sun, Wei; Bultman, Scott J.

doi:10.1016/j.molcel.2012.08.033

Cited by 683 publications

(603 citation statements)

References 51 publications

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“…However, the metabolites generated are likely not simply consequences of catabolism or anabolism but instead act as intracellular signals. The examples discussed here of succinate, HIF1␣, NAD ϩ , and sirtuins are part of a broader picture, including other metabolites such as ␣-KG (which is used by up to 33 enzymes (52), all of which modify chromatin) and butyrate (which inhibits histone deacetylases), and epigenetic modifications are likely to be a key consequence for these changes, as already indicated in tumors (53). The importance of these metabolic signals in vivo is still being investigated, but several pieces of evidence suggest that these metabolic signals play a central role in inflammation.…”

Section: Perspectivementioning

confidence: 85%

How Metabolism Generates Signals during Innate Immunity and Inflammation

McGettrick

O’Neill

2013

Journal of Biological Chemistry

197

161

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The interplay between immunity, inflammation, and metabolic changes is a growing field of research. Toll-like receptors and NOD-like receptors are families of innate immune receptors, and their role in the human immune response is well documented. Exciting new evidence is emerging with regard to their role in the regulation of metabolism and the activation of inflammatory pathways during the progression of metabolic disorders such as type 2 diabetes and atherosclerosis. The proinflammatory cytokine IL-1␤ appears to play a central role in these disorders. There is also evidence that metabolites such as NAD ؉ (acting via deacetylases such as SIRT1 and SIRT2) and succinate (which regulates hypoxia-inducible factor 1␣) are signals that regulate innate immunity. In addition, the extracellular overproduction of metabolites such as uric acid and cholesterol crystals acts as a signal sensed by NLRP3, leading to the production of IL-1␤. These observations cast new light on the role of metabolism during host defense and inflammation.

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Section: Perspectivementioning

confidence: 85%

How Metabolism Generates Signals during Innate Immunity and Inflammation

McGettrick

O’Neill

2013

Journal of Biological Chemistry

197

161

View full text Add to dashboard Cite

show abstract

“…1,2 These effects are linked to the production of short chain fatty acids (SCFAs), predominantly acetate, propionate and butyrate, which are generated by fermentation of FC by microbiota in the colon. 3 The antitumorigenic effects attributed to SCFAs are, in turn, thought to arise from their altering…”

Section: Introductionmentioning

confidence: 99%

Cationic lipid-based nanoparticles mediate functional delivery of acetate to tumor cells in vivo leading to significant anticancer effects

Brody¹,

Sahuri-Arisoylu²,

Parkinson³

et al. 2017

IJN

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Metabolic reengineering using nanoparticle delivery represents an innovative therapeutic approach to normalizing the deregulation of cellular metabolism underlying many diseases, including cancer. Here, we demonstrated a unique and novel application to the treatment of malignancy using a short-chain fatty acid (SCFA)-encapsulated lipid-based delivery system – liposome-encapsulated acetate nanoparticles for cancer applications (LITA-CAN). We assessed chronic in vivo administration of our nanoparticle in three separate murine models of colorectal cancer. We demonstrated a substantial reduction in tumor growth in the xenograft model of colorectal cancer cell lines HT-29, HCT-116 p53+/+ and HCT-116 p53−/−. Nanoparticle-induced reductions in histone deacetylase gene expression indicated a potential mechanism for these anti-proliferative effects. Together, these results indicated that LITA-CAN could be used as an effective direct or adjunct therapy to treat malignant transformation in vivo.

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“…However, most cancer cells prefer to utilize glucose as an energy source even under abundant oxygen conditions, so colon cancer cells cannot use butyrate efficiently, which enhances its anticancer effects (6).…”

Section: Introductionmentioning

confidence: 99%

Butyrate-mediated acquisition of chemoresistance by human colon cancer cells

et al. 2016

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Abstract. Butyrate is a short-chain fatty acid produced by the intestinal microflora and it not only induces apoptosis but also inhibits the proliferation of cancer cells. Recently, it has been reported that butyrate may cause resistance in colon cancer cells. Therefore, we investigated the effects of increased resistance to butyrate in HCT116 colon cancer cells. We established HCT116 cells resistant to butyrate (HCT116/ BR) by treating HCT116 parental cells (HCT116/PT) with increasing concentrations of butyrate to a maximum of 1.6 mM for 3 months. The butyrate concentrations that inhibited cell growth by 50% (IC 50 ) were 0.508 and 5.50 mM in HCT116/PT and HCT116/BR cells. The values after treatment with paclitaxel, 5-fluorouracil (5-FU), doxorubicin and trichostatin A (TSA) were 2.42, 2.36, 4.31 and 11.3-fold higher, respectively, in HCT116/BR cells compared with HCT116/PT cells. The protein expression of drug efflux pumps, such as P-glycoprotein (P-gp), breast cancer-resistant protein (BCRP) and the multidrug resistance associated protein 1 (MRP1), did not differ between HCT116/PT and HCT116/BR cells. The expression level of the anti-apoptotic Bcl-xL protein was increased while those of pro-apoptotic Bax and Bim proteins were reduced in HCT116/BR cells. There were no significant differences in cell motility and invasion. This study suggests that exposure of colon cancer cells to butyrate results in development of resistance to butyrate, which may play a role in the acquisition of chemoresistance in colon cancer. IntroductionColon cancer is one of the most common cancers and its prevalence is increasing gradually due to changes in lifestyle (1).Epidemiological studies have attempted to elucidate an association between a high-fiber diet and decreased incidence and progression of colon cancer. Butyrate is a short-chain fatty acid that is naturally produced by the intestinal microflora during dietary fiber fermentation and has been suggested as a target for colon cancer therapy because it inhibits cell proliferation and causes apoptosis in colon cancer cells (2). Butyrate suppresses cell proliferation by causing cell cycle arrest at the G 1 and G 2 phases, which involves cyclin D1 and retinoblastoma (Rb) signaling (3). In addition, butyrate is a histone deacetylase (HDAC) inhibitor, similar to trichostatin A(TSA), and results in apoptosis by increasing the expression of pro-apoptotic proteins, such as Bak, Bad and Bim, and decreasing that of anti-apoptotic proteins, such as Bcl-2 and Bcl-xL (4).Butyrate plays an important role in normal colonocytes as a major energy source and promotes their proliferation (5). However, most cancer cells prefer to utilize glucose as an energy source even under abundant oxygen conditions, so colon cancer cells cannot use butyrate efficiently, which enhances its anticancer effects (6).Recently, it has been reported that butyrate may trigger resistance in colon cancer cells (7). As mentioned above, butyrate is a natural product of dietary fiber fermentation to which colonocytes are c...

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

Cited by 683 publications

References 51 publications

How Metabolism Generates Signals during Innate Immunity and Inflammation

How Metabolism Generates Signals during Innate Immunity and Inflammation

Cationic lipid-based nanoparticles mediate functional delivery of acetate to tumor cells in vivo leading to significant anticancer effects

Butyrate-mediated acquisition of chemoresistance by human colon cancer cells

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