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.

中文翻译：

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ACSL4通过ERK / FBW7 / c-Myc轴介导的c-Myc稳定性促进肝细胞癌的进展。

肝细胞癌（HCC）是高度异质，多基因驱动的恶性肿瘤。长链酰基辅酶A合成酶4（ACSL4）在花生四烯酸（AA）代谢中具有关键作用。但是，在肝癌中其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将ACSL4鉴定为AFP高亚型HCC的新标记。ACSL4在HCC样本中经常上调，并与不良预后相关。从功能上讲，ACSL4基因敲低导致细胞生长减少，而异位ACSL4表达则促进了体内外的肿瘤形成。从机理上讲，ACSL4通过泛素-蛋白酶体系统以ERK / FBW7依赖性方式稳定癌蛋白c-Myc。使用siRNA或其抑制剂10058-F4，c-Myc耗竭可部分削弱ACSL4升高介导的细胞生长能力。相反，通过FBW7敲低c-Myc过表达，部分地逆转了ACSL4沉默的影响。临床上，ACSL4的表达与肝癌中c-Myc呈正相关。总之，ACSL4是AFP高亚型HCC的新型标志物。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，并且可能是有价值的预后生物标志物和潜在的HCC治疗靶标。ACSL4是AFP高亚型HCC的新型标志物。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，并且可能是有价值的预后生物标志物和潜在的HCC治疗靶标。ACSL4是AFP高亚型HCC的新型标志物。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，并且可能是有价值的预后生物标志物和潜在的HCC治疗靶标。