Suppression of ACADM-Mediated Fatty Acid Oxidation Promotes Hepatocellular Carcinoma via Aberrant CAV1/SREBP1 Signaling

Cancer Res. 2021 Jul 1;81(13):3679-3692. doi: 10.1158/0008-5472.CAN-20-3944. Epub 2021 May 11.


Lipid accumulation exacerbates tumor development, as it fuels the proliferative growth of cancer cells. The role of medium-chain acyl-CoA dehydrogenase (ACADM), an enzyme that catalyzes the first step of mitochondrial fatty acid oxidation, in tumor biology remains elusive. Therefore, investigating its mode of dysregulation can shed light on metabolic dependencies in cancer development. In hepatocellular carcinoma (HCC), ACADM was significantly underexpressed, correlating with several aggressive clinicopathologic features observed in patients. Functionally, suppression of ACADM promoted HCC cell motility with elevated triglyceride, phospholipid, and cellular lipid droplet levels, indicating the tumor suppressive ability of ACADM in HCC. Sterol regulatory element-binding protein-1 (SREBP1) was identified as a negative transcriptional regulator of ACADM. Subsequently, high levels of caveolin-1 (CAV1) were observed to inhibit fatty acid oxidation, which revealed its role in regulating lipid metabolism. CAV1 expression negatively correlated with ACADM and its upregulation enhanced nuclear accumulation of SREBP1, resulting in suppressed ACADM activity and contributing to increased HCC cell aggressiveness. Administration of an SREBP1 inhibitor in combination with sorafenib elicited a synergistic antitumor effect and significantly reduced HCC tumor growth in vivo. These findings indicate that deregulation of fatty acid oxidation mediated by the CAV1/SREBP1/ACADM axis results in HCC progression, which implicates targeting fatty acid metabolism to improve HCC treatment. SIGNIFICANCE: This study identifies tumor suppressive effects of ACADM in hepatocellular carcinoma and suggests promotion of β-oxidation to diminish fatty acid availability to cancer cells could be used as a therapeutic strategy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl-CoA Dehydrogenase / antagonists & inhibitors*
  • Acyl-CoA Dehydrogenase / genetics
  • Acyl-CoA Dehydrogenase / metabolism
  • Animals
  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology*
  • Caveolin 1 / genetics
  • Caveolin 1 / metabolism*
  • Cell Proliferation
  • Fatty Acids / chemistry*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Lipid Metabolism
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Oxidation-Reduction
  • Prognosis
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • Biomarkers, Tumor
  • CAV1 protein, human
  • Caveolin 1
  • Fatty Acids
  • SREBF1 protein, human
  • Sterol Regulatory Element Binding Protein 1
  • Acyl-CoA Dehydrogenase