Suppression of fatty acid oxidation by caveolin-1 contributes to hepatocellular carcinoma progression

Abstract

Liver cancer is the second leading cause of cancer deaths worldwide, with HCC accounting for ~75% of cases. One of the metabolic changes in HCC is the way that fatty acids are metabolised in cancer cells. Cav1 has been reported to be a metastasis promoter in HCC. Mutations in the ACADM gene results in the accumulation of non-degraded fatty acids in tissues, leading to eventual liver damage. Here, we delineate a new molecular pathway in which oncogenic Cav1 downregulates ACADM leading to the dysregulation of beta-oxidation in HCC. In this study, we found that Cav1 upregulated HCC cell growth and motility via the suppression of fatty acid oxidation. In Cav1 knockdown cells, ACADM was upregulated at the transcriptional and translational levels. Suppression of ACADM in Cav1 knockdown cells restored HCC cell growth, motility and cellular lipid content. Upon further investigation, it was found that Cav1 and ACADM expressions showed a significant negative correlation in HCC tissues and cell lines. Examination of the levels of ACADM in HCC clinical samples revealed that it was downregulated in 64% of the cases. The overall ACADM mRNA level was significantly downregulated in HCC tissues versus nontumorous liver tissues and its underexpression also correlated to other clinicopathological parameters such as venous invasion and rapid cell differentiation. ACADM knockdown clones established in HCC cell lines showed elevated levels of cellular lipid content and increased abilities of migration, invasion and anchorage independent growth, therefore enhancing the cell aggressiveness in HCC. Our findings revealed the tight association between ACADM underexpression with the aggressive HCC clinical features suggesting targeting Cav1, negative regulator of ACADM, as a therapeutic intervention in HCC. Further investigation of the interaction between these two genes will be crucial in understanding the underlying basis of HCC tumorigenesis and disease progression. References NIH. Medium-chain acyl-coenzyme A dehydrogenase deficiency. 2017. Tang, Y., Zeng, X., He, F. et al. Caveolin-1 is related to invasion, survival, and poor prognosis in hepatocellular cancer. Med Oncol (2012) 29: 977. Wang M, Han J, Xing H, et al. Dysregulated fatty acid metabolism in hepatocellular carcinoma. Hepat Oncol. 2017;3(4):241–251. World Health Organization. World Cancer Report. 2014. pp. Chapters 1.1 and 5.6.