ACSL4 promotes hepatocellular carcinoma progression via c-Myc stability mediated by ERK/FBW7/c-Myc axis
ACSL4 promotes hepatocellular carcinoma progression via c-Myc stability mediated by ERK/FBW7/c-Myc axis
复制标题
ACSL4 通过 ERK/FBW7/c-Myc 轴介导的 c-Myc 稳定性促进肝细胞癌进展
DOI：
10.1038/s41389-020-0226-z
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发表时间：
2020-04-29
期刊：
影响因子：
6.2
通讯作者：
Zheng, Shusen
中科院分区：
文献类型：
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作者：
Chen, Junru;Ding, Chaofeng;Zheng, Shusen
肝细胞癌（HCC）是一种高度异质性、多基因驱动的恶性肿瘤。长链酰基辅酶a合成酶4 （ACSL4）是一种在花生四烯酸（AA）代谢中起关键作用的酶。然而，其在HCC中的功能和潜在的分子机制仍未完全阐明。在这里，我们通过转录组分析发现ACSL4是AFP高亚型HCC的新标志物。ACSL4在HCC样本中经常上调，并与不良预后相关。功能上，ACSL4敲低导致细胞生长下降，而异位ACSL4表达促进体外和体内肿瘤形成。机制上，ACSL4通过泛素-蛋白酶体系统以ERK/ fbw7依赖的方式稳定癌蛋白c-Myc。用siRNA或其抑制剂10058-F4去除了c-Myc，可以部分减弱ACSL4升高介导的细胞生长能力。相反，通过FBW7敲低c-Myc过表达，ACSL4沉默的作用部分被逆转。临床上，HCC中ACSL4的表达与c-Myc呈正相关。综上所述，ACSL4是一种新的AFP高亚型HCC标志物。我们的数据揭示了ACSL4通过ERK/FBW7/c-Myc轴介导的c-Myc稳定性促进HCC进展的新机制，可能是HCC中有价值的预后生物标志物和潜在的治疗靶点。
Hepatocellular carcinoma (HCC) is a highly heterogeneous, multigene-driven malignant tumor. Long chain acyl-CoA synthetase 4 (ACSL4), an enzyme has pivotal roles in arachidonic acid (AA) metabolism. However, its function and the underlying molecular mechanisms in HCC are still not fully elucidated. Here, we identified ACSL4 as a novel marker for AFP high subtype HCC through transcriptome profiling. ACSL4 was frequently upregulated in HCC samples and associated with poor prognosis. Functionally, ACSL4 knockdown resulted in decreased cell growth, whereas ectopic ACSL4 expression facilitated tumor formation in vitro and in vivo. Mechanistically, ACSL4 stabilized the oncoprotein c-Myc through ubiquitin–proteasome system in an ERK/FBW7-dependent manner. Cell growth ability mediated by ACSL4 elevation was partly attenuated by c-Myc depletion using siRNA or its inhibitor 10058-F4. In contrast, the effects of ACSL4 silencing were partially reversed by c-Myc overexpression via FBW7 knockdown. Clinically, ACSL4 expression was positively correlated with c-Myc in HCC. In conclusion, ACSL4 is a novel marker for AFP high subtype HCC. Our data uncovered a new mechanism by which ACSL4 promotes HCC progression via c-Myc stability mediated by ERK/FBW7/c-Myc axis and could be a valuable prognostic biomarker and a potential therapeutic target in HCC.