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

Abstract

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.

Lipid alterations in chronic liver disease and liver cancer

“… 242 Furthermore, downregulation of acylcarnitine translocase (SLC25A20) in the mitochondrial matrix is observed in both HCC and CCA (TCGA, www.firebrowse.org ) and was shown to suppress FAO and promote HCC proliferation as well as metastasis. 243 Furthermore, enzymes in the FAO process, such as medium-chain acyl-CoA dehydrogenase 244 and long-chain acyl-CoA dehydrogenase, 245 have potential tumour suppressor roles in HCC. 244 , 245 Therefore, FA utilisation for structural and messenger molecules, rather than storage or energy sources, supports HCC development and progression.…”

“… 243 Furthermore, enzymes in the FAO process, such as medium-chain acyl-CoA dehydrogenase 244 and long-chain acyl-CoA dehydrogenase, 245 have potential tumour suppressor roles in HCC. 244 , 245 Therefore, FA utilisation for structural and messenger molecules, rather than storage or energy sources, supports HCC development and progression.…”

A Fatty Acid Metabolism Signature Associated With Clinical Therapy in Clear Cell Renal Cell Carcinoma

“…It had been reported that ACADM is associated with the progression of some tumors, especially those closely related to lipid metabolism, such as neuroblastoma and breast cancer (Ma et al, 2021;Hsieh et al, 2019;Yu et al, 2019). Interestingly, we found that ACADM plays an anticancer role in most tumors such as hepatocellular carcinoma and neuroblastoma (Hsieh et al, 2019;Ma et al, 2021). However, it has been reported that ACADM enhances the invasion and metastasis ability of breast cancer cells (Yu et al, 2019).…”

Lipid Metabolism and Cancer

“…Medium-chain acyl coenzyme dehydrogenase (ACADM) is a functional component that promotes β-oxidation, and SREBP-1 is a negative transcriptional regulator of ACADM. Cav1 is an important factor involved in tumorigenesis and progression of many cancers, and Cav1 can regulate fatty acid metabolism by activating SREBP-1, thereby inhibiting ACADM in HCC [ 85 ].…”