Tamura Kenji, Makino Asami, Hullin-Matsuda Françoise, Kobayashi Toshihide, Furihata Mutsuo, Chung Suyoun, Ashida Shingo, Miki Tsuneharu, Fujioka Tomoaki, Shuin Taro, Nakamura Yusuke, Nakagawa Hidewaki
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Cancer Res. 2009 Oct 15;69(20):8133-40. doi: 10.1158/0008-5472.CAN-09-0775. Epub 2009 Oct 13.
A number of epidemiologic studies have indicated a strong association between dietary fat intake and prostate cancer development, suggesting that lipid metabolism plays some important roles in prostate carcinogenesis and its progression. In this study, through our genome-wide gene expression analysis of clinical prostate cancer cells, we identified a novel lipogenic gene, ELOVL7, coding a possible long-chain fatty acid elongase, as overexpressed in prostate cancer cells. ELOVL7 expression is regulated by the androgen pathway through SREBP1, as well as other lipogenic enzymes. Knockdown of ELOVL7 resulted in drastic attenuation of prostate cancer cell growth, and it is notable that high-fat diet promoted the growth of in vivo tumors of ELOVL7-expressed prostate cancer. In vitro fatty acid elongation assay and fatty acid composition analysis indicated that ELOVL7 was preferentially involved in fatty acid elongation of saturated very-long-chain fatty acids (SVLFA, C20:0 approximately ). Lipid profiles showed that knockdown of ELOVL7 in prostate cancer cells affected SVLFAs in the phospholipids and the neutral lipids, such as cholesterol ester. Focusing on cholesterol ester as a source of de novo steroid synthesis, we show that ELOVL7 affected de novo androgen synthesis in prostate cancer cells. These findings suggest that EVOLV7 could be involved in prostate cancer growth and survival through the metabolism of SVLFAs and their derivatives, could be a key molecule to elucidate the association between fat dietary intake and prostate carcinogenesis, and could also be a promising molecular target for development of new therapeutic or preventive strategies for prostate cancers.
多项流行病学研究表明，膳食脂肪摄入与前列腺癌发生之间存在密切关联，这表明脂质代谢在前列腺癌的发生及其进展中发挥着重要作用。在本研究中，通过对临床前列腺癌细胞进行全基因组基因表达分析，我们鉴定出一个新的脂肪生成基因ELOVL7，它编码一种可能的长链脂肪酸延长酶，在前列腺癌细胞中过表达。ELOVL7的表达受雄激素途径通过SREBP1以及其他脂肪生成酶的调控。敲低ELOVL7导致前列腺癌细胞生长急剧减弱，值得注意的是，高脂饮食促进了表达ELOVL7的前列腺癌体内肿瘤的生长。体外脂肪酸延长试验和脂肪酸组成分析表明，ELOVL7优先参与饱和超长链脂肪酸（SVLFA，约C20:0）的脂肪酸延长。脂质谱分析表明，敲低前列腺癌细胞中的ELOVL7会影响磷脂和中性脂质（如胆固醇酯）中的SVLFA。以胆固醇酯作为从头合成类固醇的来源，我们发现ELOVL7影响前列腺癌细胞中从头合成雄激素的过程。这些发现表明，ELOVL7可能通过SVLFA及其衍生物的代谢参与前列腺癌的生长和存活，可能是阐明膳食脂肪摄入与前列腺癌发生之间关联的关键分子，也可能是开发前列腺癌新治疗或预防策略的有前景的分子靶点。
