Novel Lipogenic Enzyme ELOVL7 Is Involved in Prostate Cancer Growth through Saturated Long-Chain Fatty Acid Metabolism
Novel Lipogenic Enzyme ELOVL7 Is Involved in Prostate Cancer Growth through Saturated Long-Chain Fatty Acid Metabolism
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DOI：
10.1158/0008-5472.can-09-0775
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发表时间：
2009-10-15
期刊：
影响因子：
11.2
通讯作者：
Nakagawa, Hidewaki
中科院分区：
文献类型：
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作者：
Tamura, Kenji;Makino, Asami;Nakagawa, Hidewaki
许多流行病学研究表明膳食脂肪摄入量与前列腺癌的发展之间存在密切关系，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。在这项研究中，通过对临床前列腺癌细胞的全基因组基因表达分析，我们鉴定了一种新的脂肪生成基因 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度表达。 ELOVL7 表达受雄激素途径通过 SREBP1 以及其他脂肪生成酶的调节。 ELOVL7的敲低导致前列腺癌细胞生长的急剧减弱，值得注意的是，高脂肪饮食促进了表达ELOVL7的前列腺癌体内肿瘤的生长。体外脂肪酸延伸实验和脂肪酸组成分析表明，ELOVL7优先参与饱和极长链脂肪酸（SVLFA，C20:0类似）的脂肪酸延伸。脂质谱显示，前列腺癌细胞中 ELOVL7 的敲低会影响磷脂和中性脂质（例如胆固醇酯）中的 SVLFA。重点关注胆固醇酯作为类固醇从头合成的来源，我们发现 ELOVL7 影响前列腺癌细胞中雄激素的从头合成。这些发现表明，EVOLV7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，可能是阐明脂肪饮食摄入与前列腺癌发生之间关系的关键分子，也可能是开发前列腺癌新治疗或预防策略的有希望的分子靶点。 [癌症研究 2009;69(20):8133-40]
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 similar to). 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. [Cancer Res 2009;69(20):8133-40]