ACADL plays a tumor-suppressor role by targeting Hippo/YAP signaling in hepatocellular carcinoma
ACADL plays a tumor-suppressor role by targeting Hippo/YAP signaling in hepatocellular carcinoma
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ACADL 通过靶向肝细胞癌中的 Hippo/YAP 信号传导发挥肿瘤抑制作用
DOI：
10.1038/s41698-020-0111-4
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发表时间：
2020-03-25
影响因子：
7.9
通讯作者：
Wang, Hongyang
中科院分区：
文献类型：
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作者：
Zhao, Xiaofang;Qin, Wenhao;Wang, Hongyang
长链酰基辅酶A脱氢酶（ACADL）是一种线粒体酶，催化脂肪酸氧化的第一步，但ACADL在肿瘤生物学中的作用仍然很大程度上未知。在此，我们发现ACADL在肝细胞癌（HCC）中频繁下调，其低表达与HCC患者不良的临床预后显着相关。在 HCC 细胞中恢复 ACADL 的表达，通过抑制 Hippo/YAP 信号传导导致细胞周期停滞和生长抑制，这通过 YAP 核积累和下游靶基因表达的减少来证明。 XMU-MP-1 重新激活 YAP 减弱了 ACADL 对 HCC 生长的抑制作用。更重要的是，YAP的核积累与HCC标本中ACADL表达水平呈负相关，YAP抑制剂维替泊芬有效抑制ACADL低表达的HCC类器官的生长。总之，我们的研究结果强调了 ACADL 在调节 HCC 生长方面的新功能，并且靶向 ACADL/Yap 可能是 HCC 精准治疗的潜在策略。
Long-chain acyl-CoA dehydrogenase (ACADL) is a mitochondrial enzyme that catalyzes the initial step of fatty acid oxidation, but the role of ACADL in tumor biology remains largely unknown. Here, we found that ACADL was frequently downregulated in hepatocellular carcinoma (HCC), and its low expression was significantly correlated with poor clinical prognosis of HCC patients. Restoring the expression of ACADL in HCC cells resulted cell cycle arrest and growth suppression through suppressing Hippo/YAP signaling evidenced by decreased YAP nuclear accumulation and downstream target genes expression. Reactivation of YAP by XMU-MP-1 diminished the inhibitory effect of ACADL on HCC growth. More importantly, the nuclear accumulation of YAP was negatively correlated with ACADL expression levels in HCC specimens, and YAP inhibitor verteporfin effectively suppressed growth of HCC organoids with low ACADL expression. Together, our findings highlight a novel function of ACADL in regulating HCC growth and targeting ACADL/Yap may be a potential strategy for HCC precise treatment.