ACADL plays a tumor-suppressor role by targeting Hippo/YAP signaling in hepatocellular carcinoma

Xiaofang Zhao,Hongyang Wang,Rongyang Dai,Zhishi Yang,Wenhao Qin,Youhai Jiang,Yao Chen,Hao Shen,Jing Fu,Bo Yuan

doi:10.1038/s41698-020-0111-4

Abstract

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.

Highlights

Hepatocellular carcinoma (HCC), the major type of liver cancer, is the fifth most prevalent malignancy and the third leading cause of cancer-related death worldwide[1,2]
Our analysis revealed that the mRNA levels of ACADL dramatically decreased in HCC tissues (n = 369) compared with normal livers (n = 160) (Fig. 1a)
A recent paper demonstrated that the expression of ACADL was downregulated by HIF-1α under hypoxic conditions in human HCC cells, and decreased ACADL expression led to cancer progression through promoting accumulation of unsaturated fat[9]

Summary

Introduction

Hepatocellular carcinoma (HCC), the major type of liver cancer, is the fifth most prevalent malignancy and the third leading cause of cancer-related death worldwide[1,2]. Rapid unlimited cell proliferation is the most malignant phenotype of cancer cells. As a highly heterogeneous tumor, some regulators attributed to HCC progression has been identified, the molecular mechanisms underlying the rapid cell proliferation and growth of HCC cells are largely unknown[3]. There is an urgent need for more complete understanding of the molecular mechanisms involved in deregulated HCC cell proliferation, which could help improve therapeutic strategies. ACADL deficiency mice have severe hepatic and cardiac lipidosis, hypoglycemia, elevated serum-free fatty acids and hepatic insulin resistance caused by impaired fatty acid oxidation[5,6]

Methods

Results

Conclusion