Sterol regulatory element-binding protein-1 participates in the regulationof fatty acid synthase expression in colorectal neoplasia

Endogenous fatty acid synthesis has been observed in certain rapidly prolif erating normal and neoplastic tissues. Sterol regulatory element-binding pr oteins (SREBPs) are transcription factors that regulate the expression of l ipogenic genes including fatty acid synthase (FAS), the major biosynthetic enzyme for fatty acid synthesis. We have previously shown that SREBP-1, FAS , and Ki-67, a proliferation marker, colocalized in the crypts of the fetal gastrointestinal tract epithelium. This study sought to determine whether SREBP-1 participates in the regulation of proliferation-associated fatty ac id synthesis in colorectal neoplasia. An immunohistochemical analysis of SR EBP-1, FAS, and Ki-67 expression in 25 primary human colorectal carcinoma s pecimens showed colocalization in 22 of these. To elucidate a functional li nkage between SREBP-1 activation and proliferation-associated FA synthesis, SREBP-1 and FAS content were assayed during the adaptive response of cultu red HCT116 colon carcinoma cells to pharmacological inhibition of FA synthe sis. Cerulenin and TOFA each inhibited the endogenous synthesis of fatty ac ids in a dose-dependent manner and each induced increases in both precursor and mature forms of SREBP-1. Subsequently, both the transcriptional activi ty of the FAS promoter in a luciferase reporter gene construct and the FAS expression increased. These results demonstrate that tumor cells recognize and respond to a deficiency in endogenous fatty acid synthesis by upregulat ing both SREBP-1 and FAS expression and support the model that SREBP-1 part icipates in the transcriptional regulation of lipogenic genes in colorectal neoplasia. (C) 2000 Academic Press.