Overexpression of fatty acid synthase is associated with palmitoylation of Wnt1 and cytoplasmic stabilization of beta-catenin in prostate cancer.
Overexpression of fatty acid synthase is associated with palmitoylation of Wnt1 and cytoplasmic stabilization of beta-catenin in prostate cancer.
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DOI：
10.1038/labinvest.2008.97
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发表时间：
2008-12
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--
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中科院分区：
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脂肪酸合成酶(FASN)是脂蛋白合成的关键代谢酶，在多种人类癌症中高度表达，过表达时表现出抗凋亡、促增殖等致癌特性。到目前为止，还没有确定任何机制来解释FASN在前列腺癌中的致癌作用。我们建立了高表达FASN的永生化前列腺上皮细胞(IPrEC)，并发现在免疫沉淀的WNT-1中，与不高表达FASN的同基因细胞相比，由FASN从头合成的棕榈酸酯中14C-乙酸酯的掺入显著增加。FASN过表达导致细胞膜和细胞质β-连环蛋白的积聚和激活，而短发夹状RNA(ShRNA)敲除FASN导致β-连环蛋白激活程度降低。在裸鼠体内原位移植高表达FASN的iPrEC细胞可导致高表达β-连环蛋白的侵袭性肿瘤。在862例前列腺癌患者中，在计算机减去细胞膜β-连环蛋白信号后，FASN与细胞质(稳定)的β-连环蛋白免疫染色显著相关(P<；0.001，Spearman‘s Rho=0.33)。我们认为，通过WNT-1的棕榈酸化和随后激活该途径使β-连环蛋白在细胞质中稳定是前列腺癌FASN致癌的一个潜在机制。
Fatty acid synthase (FASN), a key metabolic enzyme for liponeogenesis highly expressed in several human cancers, displays oncogenic properties such as resistance to apoptosis and induction of proliferation when overexpressed. To date, no mechanism has been identified to explain the oncogenicity of FASN in prostate cancer. We generated immortalized prostate epithelial cells (iPrEC) overexpressing FASN, and found that 14C-acetate incorporation into palmitate synthesized de novo by FASN was significantly elevated in immunoprecipitated Wnt-1 when compared to isogenic cells not overexpressing FASN. Overexpression of FASN caused membranous and cytoplasmic β-catenin protein accumulation and activation, while FASN knockdown by short hairpin RNA (shRNA) resulted in a reduction in the extent of β-catenin activation. Orthotopic transplantation of iPrEC cells overexpressing FASN in nude mice resulted in invasive tumors that overexpressed β-catenin. A strong significant association between FASN and cytoplasmic (stabilized) β-catenin immunostaining was found in 862 cases of human prostate cancer after computerized subtraction of the membranous β-catenin signal (P<0.001, Spearman’s rho=0.33). We propose that cytoplasmic stabilization of β-catenin through palmitoylation of Wnt-1 and subsequent activation of the pathway is a potential mechanism of FASN oncogenicity in prostate cancer.
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