Elongation of Very Long Chain Fatty Acids Like- 3 (Elovl3) is activated by ZHX2 and is a regulator of cell cycle progression

Abstract

Zinc fingers and homeoboxes 2 (ZHX2) functions as a tumor suppressor in several models of hepatocellular carcinoma (HCC), presumably through its control of target genes. Previous microarray data suggested that Elongation of Very Long Chain Fatty Acids 3 (Elovl3), a member of the Elovl family which synthesize very long chain fatty acids (VLCFAs), is a putative ZHX2 target gene. VLCFAs are core component of ceramides and other bioactive sphingolipids, which are often dysregulated in diseases, including HCC. Since several previously identified ZHX2 targets become dysregulated in HCC, we investigated the relationship between ZHX2 and Elovl3 in liver damage and HCC. Here, using mouse and cell models, we demonstrate that Zhx2 positively regulates Elovl3 expression in the liver and that male-biased hepatic Elovl3 expression is established between 4-8 weeks of age in mice. Elovl3 is dramatically repressed in mouse models of liver regeneration and HCC and the reduced Elovl3 levels in the regenerating liver are associated with changes in hepatic very long chain fatty acids. Human hepatoma cell lines with forced Elovl3 expression have lower rates of cell growth; analysis of synchronized cells indicate that this reduced proliferation correlates with cells stalling in S-phase. Taken together, these data indicate that Elovl3 expression helps regulate cellular proliferation, possibly through control of VLCFAs, and its repression may be a contributing factor to HCC and explain, in part, the function of ZHX2 as a suppressor of HCC progression.