Isolation of the exon‐switching variant, CYP4F2b, from human hepatic carcinoma (HCC) and its role in modulating epithelial‐mesenchymal transition (EMT) through Twist2.

Abstract

Cytochrome P450 IV (CYP4) are a family of omega‐hydroxylase enzymes. We have previously shown that these fatty acid omega‐hydroxylases function in the hydroxylation of various chain‐length saturated and unsaturated fatty acids in the endoplasmic reticulum. These dicarboxylate products then undergo peroxisomal β‐oxidation, yielding shorter chain fatty acids. In humans, the CYP4F family members hydroxylate long‐chain fatty acid (>C16) and the bioactive eicosanoids, arachidonic acid (HETE) and pro‐inflammatory leukotrienes B4 (LTB4). In the human liver, CYP4F2a metabolizes long‐chain fatty acids and arachidonic acid to the vasoactive 20‐HETE. We have identified a new variant, CYP4F2b from human hepatic carcinoma that is produced from the CYP4F2 gene by exon switching. We have compared the expression of CYP4 members in human HCC and matched healthy human liver. We observed increased expression of CYP4F2b in HCC compared to controls, as well as increased fatty acid omega‐hydroxylation, with associated elevations of acetyl‐CoA/acetate in HCC, and decreased activity and expression of the acetyl‐CoA thioesterase 12 (ACOT12). Increased acetyl‐CoA levels activate the basic helix‐loop‐helix (bHLH) transcription factor Twist2, which initiates an epithelial‐mesenchymal cell transition (EMT). We propose that increased omega‐hydroxylation of fatty acids by CYP4F2b and subsequent peroxisomal β‐oxidation increases cellular acetyl‐CoA levels in HCC, leading to activation of Twist2 and progression of EMT.Support or Funding InformationNEOMED foundation