Integrative Transcriptomic Network Analysis of Butyrate Treated Colorectal Cancer Cells

Abstract

Diet-derived histone deacetylase inhibitor (HDACi), butyrate, alters global acetylation and consequently global gene expression in colorectal cancer (CRC) cells to exert its anticancer effects. Aberrant microRNA (miRNA) expression contributes to CRC development and progression. Butyrate-mediated modulation of microRNA (miRNA) expression remains under-investigated. This study employed a systems biology approach to gain a comprehensive understanding of the complex miRNA-mRNA interactions contributing to the butyrate response in CRC cells. Next-generation sequencing, gene ontology (GO) and pathway enrichment analyses were utilized to reveal the extent of butyrate-mediated gene regulation in CRC cells. Changes in cell proliferation, apoptosis, the cell cycle and gene expression induced by miRNAs and target gene knockdown in CRC cells were assessed. Butyrate induced differential expression of 113 miRNAs and 2447 protein-coding genes in HCT116 cells. Butyrate also altered transcript splicing of 1591 protein-coding genes. GO, and pathway enrichment analyses revealed the cell cycle to be a central target of the butyrate response. Two butyrate-induced miRNAs, miR-139 and miR-542, acted cooperatively with butyrate to induce apoptosis and reduce CRC cell proliferation by regulating target genes, including cell cycle-related EIF4G2 and BIRC5. EIF4G2 RNA interference mimicked the miR-139-mediated reduction in cell proliferation. The cell cycle is a critical pathway involved in the butyrate response of CRC cells. These findings reveal novel roles for miRNAs in the cell cycle-related, anticancer effects of butyrate in CRC cells.

The Role of Diet and Lifestyle in Early-Onset Colorectal Cancer: A Systematic Review

“…The most likely mechanism for these effects is higher acetylation of histones [ 141 ]. Some studies have also claimed a connection between butyrate and the stability and translation of micro-RNA [ 142 ], specifically those micro-RNAs that modulate the expression of oncogenes, such as PTEN, TP53, and CDKN1A [ 143 , 144 ]. The biological link between histone acetylation, butyrate, and eoCRC is only speculative at this stage.…”

Personalized Immunotherapy in Colorectal Cancers: Where Do We Stand?

“…Despite the efforts to study CRC heterogeneity, our current knowledge in this field is just the tip of the iceberg. Expanding next-generation sequencing (NGS), single-cell sequencing, and whole-exome sequencing techniques along with the application of omics data at various levels, including genomics, epigenomics, transcriptomics, peptidomics, proteinomics, and metabolomics, could give us valuable information on the heterogeneity of CRCs (116)(117)(118)(119)(120)(121)(122)(123).…”

The Emerging Roles of Human Gut Microbiota in Gastrointestinal Cancer

“…showed that butyrate induced CRC cell apoptosis and inhibited the proliferation and invasion via upregulating miR-203 level ( 124 ); Ali et al. found that miR-139 and miR-542 acted cooperatively with butyrate to reduce CRC cell proliferation and induce apoptosis by regulating target genes, EIF4G2 and BIRC5 ( 125 ); Hu et al. concluded that butyrate regulated p21 expression via downregulating miR-106b level ( 126 ).…”