The Impact of Sorghum Polyphenols on DNA Methylation and Signaling Pathways in Colon Cancer

Abstract

Colorectal cancer (CRC) is a major public health issue, accounting for nearly 150,000 cases annually. Because CRC correlates with inflammation and oxidative stress, exploiting the anti‐oxidative and anti‐inflammatory nature of bioactive components in our diet, such as polyphenols, could potentially contribute to the inhibition of cancer initiation. Polyphenols are an immense family of naturally occurring secondary plant metabolites found in fruits, vegetables, and cereal grains, and have been demonstrated across many in vitro and in vivo studies to protect against carcinogenesis. Not only are polyphenols implicated to impact cancer development but they may also be involved in epigenetic regulation. Abnormalities in epigenetic modifications can lead to aberrant regulation of gene expression, and depending on the genes in question, this may contribute to the cell’s ability to acquire hallmarks of cancer. New varietals of the grain Sorghum bicolor provided by the USDA contain high amounts of polyphenols, which may contribute to CRC prevention due to their strong antioxidative and anti‐carcinogenic properties. The expression of genes involved in the promotion or prevention of CRC, like the Wnt/β‐catenin signaling pathway, may be regulated via epigenetic mechanisms. We hypothesize that the high polyphenol sorghum extracts may decrease DNA methylation, thus impacting the expression genes involved in the Wnt/β‐catenin signaling pathway. For our current study, we treated HCT116 and SW480 human colon cancer cells with novel high‐polyphenol S. bicolor extracts (HP and SC) or an extract of low‐polyphenol Macia‐Sorghum for up to 48 hours. Controls included cells treated with solvent or 5 µM epigallocatechin gallate as a benchmark. Total RNA was harvested, and the mRNA expression of selected genes was quantitated via qPCR. Relative to solvent control, the high‐polyphenol S. bicolorextract HP increased mRNA expression of DNA methyltransferase 1 (DNMT1), the key enzyme that upholds methylation patterns after DNA synthesis. Furthermore, mRNA expression of DNMT3A, the enzyme responsible for de novo DNA methylation, was also increased. The SC extract significantly decreased the expression of β‐catenin while increasing expression of transcription factor 4 (TCF4), a gene that mediates the expression of pro‐tumorigenic Wnt target genes such as VEGF and cMYC. Encouraged by these preliminary findings, we will investigate mRNA and protein expression of genes that are involved in epigenetic mechanisms, as well as those of downstream signaling pathways. Our study may help elucidate the question, whether consumption of high‐polyphenol S. bicolor as part of the human diet may lead to beneficial changes in DNA methylation. Subsequently, the expression of specific genes involved in the promotion or prevention of colorectal cancer may be modified, providing a dietary intervention to CRC.