Unsaturated Fatty Acids Stimulate Tumor Growth through Stabilization of β-Catenin.
Unsaturated Fatty Acids Stimulate Tumor Growth through Stabilization of β-Catenin.
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DOI：
10.1016/j.celrep.2015.09.010
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发表时间：
2015-10-20
期刊：
影响因子：
8.8
通讯作者：
Ye J
中科院分区：
文献类型：
--
作者：
Kim H;Rodriguez-Navas C;Kollipara RK;Kapur P;Pedrosa I;Brugarolas J;Kittler R;Ye J
一些癌细胞表现出升高的游离脂肪酸（FA）水平以及高水平的β-连环蛋白（促进其生长的转录共激活物）。在这里，我们通过显示不饱和脂肪酸抑制β-连环蛋白的降解来将这两种现象联系起来。不饱和脂肪酸与Fas相关因子1（FAF 1）的UAS结构域结合，FAF 1是一种已知与β-连环蛋白结合的蛋白质，加速其降解。FA结合破坏FAF 1/β-连环蛋白复合物，阻止泛素化β-连环蛋白的蛋白酶体降解。β-连环蛋白的这种稳定机制与Wnt信号传导的机制不同，Wnt信号传导阻断β-连环蛋白的泛素化。在透明细胞肾细胞癌（ccRCC）细胞中，不饱和FA通过稳定β-连环蛋白刺激细胞增殖。在来自人ccRCC活检的组织中，不饱和FA水平升高与β-连环蛋白水平升高相关。因此，靶向FAF 1可能是治疗表现出升高的FA和β-连环蛋白的癌症的有效方法。
Some cancer cells exhibit elevated levels of free fatty acids (FAs) as well as high levels of β-catenin, a transcriptional co-activator that promotes their growth. Here we link these two phenomena by showing that unsaturated FAs inhibit degradation of β-catenin. Unsaturated FAs bind to the UAS domain of Fas-associated factor 1 (FAF1), a protein known to bind β-catenin, accelerating its degradation. FA binding disrupts the FAF1/β-catenin complex, preventing proteasomal degradation of ubiquitinated β-catenin. This mechanism for stabilization of β-catenin differs from that of Wnt signaling, which blocks ubiquitination of β-catenin. In clear cell renal cell carcinoma (ccRCC) cells, unsaturated FAs stimulated cell proliferation through stabilization of β-catenin. In tissues from biopsies of human ccRCC, elevated levels of unsaturated FAs correlated with increased levels of β-catenin. Thus, targeting FAF1 may be an effective approach to treat cancers that exhibit elevated FAs and β-catenin.