Lee Min-Young, Moon Jong-Seok, Park Sahng Wook, Koh Yoo-Kyung, Ahn Yong-Ho, Kim Kyung-Sup
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.
Biochem J. 2009 Jan 1;417(1):313-22. doi: 10.1042/BJ20080762.
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.
KLF5（Krüppel样因子5）是一种锌指转录因子，在调节细胞增殖、分化和肿瘤发生所涉及的细胞信号传导中起关键作用。在本研究中，我们发现KLF5在雄激素依赖的LNCaP前列腺癌细胞系中，通过与SREBP-1（固醇调节元件结合蛋白-1）相互作用，作为控制FASN（脂肪酸合酶）表达的关键调节因子。当用合成雄激素R1881处理细胞时，KLF5的mRNA水平升高。此外，KLF5与SREBP-1结合，并增强了SREBP-1介导的FASN启动子活性的增加。结果还表明，LNCaP前列腺癌细胞中KLF5的表达增强了FASN的表达，而小干扰RNA沉默KLF5则下调了FASN的表达。FASN基因的近端启动子区域和第一个内含子包含多个CACCC元件，这些元件介导KLF5对该基因的转录调控。然而，其他生脂和胆固醇生成基因，如编码乙酰辅酶A羧化酶、ATP-柠檬酸裂解酶、低密度脂蛋白（LDL）受体、3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）合酶和HMG-CoA还原酶的基因，由于其启动子区域缺乏CACCC元件，对KLF5的表达无反应。综上所述，这些结果表明，FASN基因是由KLF5和SREBP-1的协同作用激活的，而这种协同作用是由雄激素在雄激素依赖的前列腺癌细胞中诱导产生的。
