KLF5 enhances SREBP‐1 action in androgen‐dependent induction of FASN in prostate cancer cell line

Abstract

The Kruppel like factor 5 (KLF5) is a zinc‐finger transcription factor that plays important roles in regulating all aspects of cellular signaling involved in cell proliferation and oncogenesis. In the present study, KLF5 interacts with sterol regulatory element‐binding protein‐1 (SREBP‐1) in regulating the expression of lipogenic protein, fatty acid synthase (FASN), which plays important roles in androgen‐dependent prostate cancer cells. Genes involved in lipid metabolism, including FASN, are reported to be up‐regulated by androgens in prostate cancer cells through a coordinated cascade controlled by the activation of SREBP‐1. The promoter and intron 1 region of FASN gene contains multiple GC‐boxes that might show response to KLF5. Deletion and mutation analyses indicated that KLF5 binds to the FASN gene and strongly induces its activity. Furthermore, KLF5 protein is able to bind to SREBP‐1 and enhance the SREBP‐1 regulated activation of FASN. Transfection of KLF5 into prostate cancer cells enhanced FASN promoter activity, and conversely, silencing of KLF5 by siRNA down‐regulated FASN expression. The multiple GC motifs are scattered throughout the upstream sequence and first intron of FASN gene whereas these are scarce in the promoters of other lipogenic and cholesterogenic genes such as acetyl‐CoA carboxylase, ATP‐citrate lyase, LDL receptor, HMG‐CoA synthase and HMG‐CoA reductase, which makes FASN gene very unique among them. Taken together, FASN gene could be activated by the synergistic action of KLF5 and SREBP‐1 which is increased by androgen treatment.