Short chain fatty acid butyrate uptake reduces expressions of prostanoid EP 4 receptors and their mediation of cyclooxygenase-2 induction in HCA-7 human colon cancer cells

Naoki Kurata, Natsumi Tokashiki, Keijo Fukushima, Takaya Misao, Nanae Hasuoka, Kana Kitagawa, Masato Mashimo, John W Regan, Toshihiko Murayama, Hiromichi Fujino

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Microbiota produce short chain fatty acids (SCFAs), which are known to maintain gut homeostasis, by the fermentation of dietary fiber in the human colon. Among SCFAs, butyrate has been considered as the most physiologically effective SCFA in colorectal epithelial cells for growth and differentiation. Here we show that the E-type prostanoid 4 (EP 4 ) receptor expression level is regulated by different concentrations of butyrate, but not by other SCFAs, in human colon cancer HCA-7 cells, through sodium-coupled monocarboxylate transporter-1 (SMCT-1)-mediated uptake followed by the activation of histone acetyltransferase: cAMP response element binding protein-binding protein/p300. Of particular interest, the prostanoid EP 4 receptors are known to be expressed in normal colorectal crypt epithelial cells and maintain intestinal homeostasis by preserving mucosal integrity, while they are also known to be involved in the early stage of carcinogenesis. Thus, the links between butyrate and the expression of prostanoid EP 4 receptors are both important factors for maintaining homeostasis. Based on in silico analysis, almost half of colorectal cancer tissues have lost the expression of SMCT-1 mRNA when compared with healthy corresponding tissues. Therefore, with the collapse of homeostasis systems such as a decrease in the concentration of butyrate in colorectal tissues, or reduced butyrate uptake, there is a possibility of early stage colorectal cancer development; the transformation of normal cells to the cancerous phenotype may be due to the overexpression of prostanoid EP 4 receptors followed by excessive cyclooxygenase-2 induction, which are caused by a reduced amount of butyrate and/or its uptake, in/around colorectal epithelial cells.

Original languageEnglish (US)
Pages (from-to)308-315
Number of pages8
JournalEuropean Journal of Pharmacology
Publication statusPublished - Jun 15 2019



  • Butyrate
  • CBP/p300
  • Colorectal cancer
  • Homeostasis
  • Prostanoid EP receptor
  • SMCT-1

ASJC Scopus subject areas

  • Pharmacology

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