Hyperhomocysteinemia results from and promotes hepatocellular carcinoma via CYP450 metabolism by CYP2J2 DNA methylation

Hyperhomocysteinemia (HHcy) can result from liver disease or dysfunction and further alters intracellular lipid metabolism. Cytochrome P450 (CYP) arachidonic acid epoxygenases are expressed in human cancers and promote cancer metastasis. This study explored the interaction of Hcy and CYP450 metabolism in hepatocellular carcinoma (HCC). The levels of 4-epoxyeicosatrienoic acid (EET) isomers and their generative enzyme CYP2J2 level as well as intracellular Hcy level were higher in 42 cases of HCC than in paired non-tumor tissue. Elevated Hcy-decreased DNA methylation on SP1/AP1 binding motifs and enhancement on the CYP2J2 promoter via ERK1/2 signaling was essential for CYP2J2 upregulation and EET metabolism. Increased Hcy level enhanced the neoplastic cellular phenotype, which was reversed by CYP2J2 knockdown in vitro. Furthermore, tumor growth and size as well as patterns of CYP2J2 expression and DNA demethylation were increased with HHcy in mice induced orthotopically by 2% (wt/wt) L-methionine with or without folate deficiency. Moreover, the effect was attenuated by shRNA knockdown of CYP2J2. Thus, HHcy results from but can also promote hepatocarcingenesis via CYP450-EET metabolism by crosstalk of DNA demethylation of CYP2J2 and ERK1/2 signaling.