ACSL4 reprograms fatty acid metabolism in hepatocellular carcinoma via c-Myc/SREBP1 pathway
ACSL4 reprograms fatty acid metabolism in hepatocellular carcinoma via c-Myc/SREBP1 pathway
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ACSL4 通过 c-Myc/SREBP1 通路重编程肝细胞癌中的脂肪酸代谢
DOI：
10.1016/j.canlet.2020.12.019
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发表时间：
2021-01-21
期刊：
影响因子：
9.7
通讯作者：
Zheng, Shusen
中科院分区：
文献类型：
--
作者：
Chen, Junru;Ding, Chaofeng;Zheng, Shusen
脂代谢重编程在肝细胞癌的发生发展中起着关键作用，但其潜在的机制尚不完全清楚。长链酰基辅酶A合成酶4(ACSL4)是酰基辅酶A合成酶(acyl-CoA synthetase，ACS)家族的成员，是甲胎蛋白高亚型肝细胞癌的新标志物和癌基因。在此，我们发现了ACSL4在肝细胞癌脂质代谢中的新功能。在肝细胞癌中，ACSL4可以通过积累细胞内的甘油三酯、胆固醇和脂滴来调节新生脂肪的生成。在机制上，ACSL4通过c-Myc上调肝癌细胞中主要的脂肪生成调节因子类固醇调节元件结合蛋白1(SREBP1)及其下游的造脂酶。此外，SREBP1对于ACSL4介导的脂肪生成以及肝癌细胞的增殖和转移的调控至关重要，因为SREBP1的过表达在体内外拯救了脂肪生成的缺陷和与ACSL4抑制相关的致癌能力的降低。临床研究表明，ACSL4和SREBP1在肝细胞癌中的表达呈正相关，二者联合检测对肝细胞癌具有较强的预测价值。总之，我们的发现揭示了ACSL4调节异常脂代谢和促进肝细胞癌进展的新机制。
Lipid metabolic reprogramming plays a pivotal role in hepatocellular carcinoma (HCC) development, but the underlying mechanisms are incompletely characterized. Long chain acyl CoA synthetase 4 (ACSL4), a member of acyl-CoA synthetases (ACS) family, has been identified as a novel marker of alpha-fetoprotein-high subtype HCC and as an oncogene. Here, we identified a new function of ACSL4 in HCC lipid metabolism. ACSL4 can modulate de novo lipogenesis by accumulating intracellular triglycerides, cholesterols, and lipid droplets in HCC. Mechanistically, ACSL4 upregulates the master lipogenesis regulator sterol regulatory element binding protein 1 (SREBP1) and its downstream lipogenic enzymes in HCC cells via c-Myc. Moreover, SREBP1 is crucial for ACSL4-mediated regulation of lipogenesis as well as HCC cell proliferation and metastasis, as SREBP1 overexpression rescues lipogenic deficiency and decreased oncogenic capabilities associated with ACSL4 suppression in vitro and in vivo. Clinically, our data showed that the expression of ACSL4 was positively correlated with that of SREBP1 in HCC patients, and the combinational biomarkers showed strong predictive value for HCC. Together, our findings uncover a new mechanism by which ACSL4 modulates aberrant lipid metabolism and promotes the progression of HCC.