FAS and FACL3 are
enzymes of
fatty acid metabolism. In our previous studies, we found that FAS and FACL3 genes were
vitamin D3-regulated and involved in the antiproliferative effect of 1alpha,25(
OH)2D3 in the human
prostate cancer LNCaP cells. Here, we elucidated the mechanism behind the downregulation of FAS expression by
vitamin D3.
Triacsin C, an inhibitor of FACL3 activity, completely abolished the downregulation of FAS expression by
vitamin D3, whereas an inhibitor of FAS activity,
cerulenin, had no significant effect on the upregulation of FACL3 expression by
vitamin D3 in LNCaP cells. In human
prostate cancer PC3 cells, in which FACL3 expression is not regulated by
vitamin D3, no regulation of FAS expression was seen. This suggests that the downregulation of FAS expression by
vitamin D3 is mediated by
vitamin D3 upregulation of FACL3 expression.
Myristic acid, one of the substrates preferential for FACL3, enhanced the repression of FAS expression by
vitamin D3. The action of
myristic acid was abrogated by inhibition of FACL3 activity, suggesting that the enhancement in the downregulation of FAS expression by
vitamin D3 is due to the formation of
myristoyl-CoA. The data suggest that
vitamin D3-repression of FAS
mRNA expression is the consequence of feedback inhibition of FAS expression by long chain fatty acyl-CoAs, which are formed by FACL3 during its upregulation by
vitamin D3 in human
prostate cancer LNCaP cells.