KLF5 enhances SREBP-1 action in androgen-dependent induction of fatty acid synthase in prostate cancer cells.
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.
Lee
Min-Young
MY
Institute of Genetic Science, Center for Chronic Disease Research, Yonsei University, College of Medicine, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-752, Republic of Korea.
Moon
Jong-Seok
JS
Park
Sahng Wook
SW
Koh
Yoo-Kyung
YK
Ahn
Yong-Ho
YH
Kim
Kyung-Sup
KS
D000728:Androgens / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D047468:Immunoprecipitation; D007438:Introns / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
D000728:Androgens; C492214:KLF5 protein, human; D051741:Kruppel-Like Transcription Factors; D051780:Sterol Regulatory Element Binding Protein 1; D064429:Fatty Acid Synthases