E2F1 promotes proliferation and metastasis of clear cell renal cell carcinoma via activation of SREBP1-dependent fatty acid biosynthesis
E2F1 promotes proliferation and metastasis of clear cell renal cell carcinoma via activation of SREBP1-dependent fatty acid biosynthesis
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E2F1 通过激活 SREBP1 依赖性脂肪酸生物合成促进透明细胞肾细胞癌的增殖和转移。
DOI：
10.1016/j.canlet.2021.05.012
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发表时间：
2021-05-25
期刊：
影响因子：
9.7
通讯作者：
Zhang, Xu
中科院分区：
文献类型：
--
作者：
Shen, Donglai;Gao, Yu;Zhang, Xu
脂质合成或摄取的增强有助于癌细胞快速增殖和肿瘤进展。近年来，细胞周期调节剂除了控制细胞周期的经典功能外，还被证明参与脂质合成的控制。透明细胞肾细胞癌（ccRCC）是肾癌最常见的亚型，其特征是富含脂质的细胞质沉积。然而，脂质代谢改变与 ccRCC 肿瘤进展之间的关系尚不清楚。在这里，我们证明了 E2F 转录因子 1 (E2F1) 除了在调节细胞周期中的关键作用外，还通过上调甾醇调节元件结合蛋白 1 (SREBP1) 诱导 ccRCC 细胞中广泛的脂质积累和脂肪生成酶水平升高。 E2F1 敲除或 SREBP1 抑制会减弱 ccRCC 细胞中脂肪酸 (FA) 从头合成、细胞增殖和上皮间质转化 (EMT)。此外，在小鼠异种移植模型中，E2F1的过度表达促进了脂质储存、肿瘤生长和转移，而E2F1下调或SREBP1抑制则逆转了这些效应。在 ccRCC 患者中，高水平的 E2F1 和 SREBP1 与脂质积累增加相关，并与不良预后相关。我们的结果表明，E2F1 可以通过 SREBP1 诱导的异常脂质代谢来增加增殖和转移，这是驱动人类 ccRCC 进展的一种新型关键信号机制。
Enhanced synthesis or uptake of lipids contributes to rapid cancer cell proliferation and tumor progression. In recent years, cell cycle regulators have been shown to be involved in the control of lipid synthesis, in addition to their classical function of controlling the cell cycle. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer and is characterized by lipid-rich cytoplasmic deposition. However, the relationship between altered lipid metabolism and tumor progression in ccRCC is poorly understood. Here, we demonstrated that E2F transcription factor 1 (E2F1), in addition to its key role in regulating the cell cycle, induces extensive lipid accumulation and elevated levels of lipogenic enzymes in ccRCC cells by upregulating sterol regulatory element-binding protein 1 (SREBP1). E2F1 knockdown or SREBP1 suppression attenuated fatty acid (FA) de novo synthesis, cell proliferation and epithelial-mesenchymal transition (EMT) in ccRCC cells. Furthermore, overexpression of E2F1 promoted lipid storage, tumor growth and metastasis in a mouse xenograft model, whereas E2F1 downregulation or SREBP1 inhibition reversed these effects. In ccRCC patients, high levels of E2F1 and SREBP1 were associated with increased lipid accumulation and correlated with poor prognosis. Our results demonstrate that E2F1 can increase proliferation and metastasis through SREBP1-induced aberrant lipid metabolism, which is a novel critical signaling mechanism driving human ccRCC progression.