The Effect of Dietary Products in Combination with Gut Microbes That Enable Localized Generation of SCFA on Histone Modifications and the Pathogenesis of Colon Cancer
Introduction. Colorectal cancer (CRC) is the 3rd most common cause of cancer worldwide, with a 10x higher incidence in Western countries1. CRC is, however, increasing in some Asian countries as they shift to a Western diet2. A high fiber diet (HFD) is associated with decreased incidence of CRC3. The microbiota within the colon convert dietary fiber into short chain fatty acids (SCFAs) through fermentation3. Butyrate is a predominant SCFA produced through this process3. Studies have found butyrate to regulate histone acetylation and inhibit CRC tumor cells by increasing apoptosis, increasing cell cycle arrest, and reducing inflammation3,4,5. These findings demonstrate butyrate’s protective effects in the colon and potential in preventing or treating CRC. Methods. CRC tumors from mice treated with an HFD or low fiber diet were analyzed4. Immunohistochemistry and Western Blot analysis measured histone 3 acetylation levels (H3ac)4. ChIP assays and RT-qPCR measured H3ac levels at the promoters of FAS4. Human CRC cells treated with sodium butyrate (NaB) were compared with those lacking NaB through propidium iodide staining3. Western Blot analysis measured total cellular RNA of p21, p53, and NF-κB3. FFAR2 (a receptor activated by SCFAs) deficient and WT mice were treated with dextran sodium sulfate to induce inflammation5. Colons were visualized via H&E staining5. ChIP-qPCR measured levels of histone markers on inflammatory suppressor genes5. Results. CRC tumors from mice treated with HFD had increased H3ac levels at FAS promoters, demonstrating butyrate’s effects on apoptosis and role as a histone deacetylase (HDAC) inhibitor4. Human CRC cells treated with NaB had decreased percentage of cells in S phase with increased levels of p21, p53, and NF-κB, a transcription factor associated with p21-mediated cell cycle arrest and repressed by HDAC3. FFAR2 deficient mice had an increased number of lesions, size of lesions, and percentage of lesions in high-grade dysplasia5. There was an increase in cAMP-HDAC signaling in FFAR2 deficient mice with increased proliferation5. H3K27me3 histone marker was increased on promoter regions of inflammatory suppressors in mice lacking FFAR2. Butyrate reduced HDAC expression and increased expression of sox17 inflammatory suppressor gene. Butyrate had no effect on expression of HDAC or sox17 in FFAR2 deficient cells.5 Conclusions. Studies have found butyrate to regulate histone acetylation levels and inhibit CRC tumor cells by increasing apoptosis, increasing cell cycle arrest, and reducing inflammation3,4,5. These studies demonstrate butyrate’s protective effects, illustrating the potential benefit of an HFD in preventing CRC or functioning as future treatment.
- Villalba M, Evans SR, Vidal-Vanaclocha F, Calvo A. Role of TGF-β in metastatic colon cancer: it is finally time for targeted therapy. Cell and Tissue Research. 2017;370(1):29-39. doi:10.1007/s00441-017-2633-9.
- Sung JJ, Chiu H-M, Jung K-W, et al. Increasing Trend in Young-Onset Colorectal Cancer in Asia. The American Journal of Gastroenterology. 2019;114(2):322-329. doi:10.14309/ajg.0000000000000133.
- Saldanha SN, Kala R, Tollefsbol TO. Molecular mechanisms for inhibition of colon cancer cells by combined epigenetic-modulating epigallocatechin gallate and sodium butyrate. Experimental Cell Research. 2014;324(1):40-53. doi:10.1016/j.yexcr.2014.01.024.
- Donohoe D, Holley D, Collins L, et al. A gnotobiotic mouse model demonstrates that dietary fiber protects against colorectal tumorigenesis in a microbiota- and butyrate-dependent manner. Cancer Prevention Research. 2015;8(10 Supplement). doi:10.1158/1940-6215.prev-14-pl03-01.
- Pan P, Oshima K, Huang Y-W, et al. Loss of FFAR2 promotes colon cancer by epigenetic dysregulation of inflammation suppressors. International Journal of Cancer. 2018;143(4):886-896. doi:10.1002/ijc.31366.