KLF5 enhances SREBP-1 action in androgen-dependent induction of fatty acid synthase in prostate cancer cells

Abstract

KLF5 (Krüppel-like factor 5) is a zinc-finger transcription factor that plays a critical role in the regulation of cellular signalling involved in cell proliferation, differentiation and oncogenesis. In the present study, we showed that KLF5 acts as a key regulator controlling the expression of FASN (fatty acid synthase) through an interaction with SREBP-1 (sterol-regulatory-element-binding protein-1) in the androgen-dependent LNCaP prostate cancer cell line. The mRNA level of KLF5 increased when cells were treated with a synthetic androgen, R1881. Furthermore, KLF5 bound to SREBP-1 and enhanced the SREBP-1-mediated increase in FASN promoter activity. The results also demonstrated that the expression of KLF5 in LNCaP prostate cancer cells enhanced FASN expression, whereas silencing of KLF5 by small interfering RNA down-regulated FASN expression. The proximal promoter region and the first intron of the FASN gene contain multiple CACCC elements that mediate the transcriptional regulation of the gene by KLF5. However, other lipogenic and cholesterogenic genes, such as those encoding acetyl-CoA carboxylase, ATP-citrate lyase, the LDL (low-density lipoprotein) receptor, HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) synthase and HMG-CoA reductase are irresponsive to KLF5 expression, owing to the absence of CACCC elements in their promoter regions. Taken together, these results suggest that the FASN gene is activated by the synergistic action of KLF5 and SREBP-1, which was induced by androgen in androgen-dependent prostate cancer cells.