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Article: Suppression of ACADM-mediated fatty acid oxidation promotes hepatocellular carcinoma via aberrant Cav1/SREBP1 signaling

TitleSuppression of ACADM-mediated fatty acid oxidation promotes hepatocellular carcinoma via aberrant Cav1/SREBP1 signaling
Authors
Issue Date2021
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
Citation
Cancer Research, 2021, v. 81 n. 13, p. 3679-3692 How to Cite?
AbstractLipid 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.
Persistent Identifierhttp://hdl.handle.net/10722/302127
ISSN
2023 Impact Factor: 12.5
2023 SCImago Journal Rankings: 3.468
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorMa, APY-
dc.contributor.authorYeung, CLS-
dc.contributor.authorTey, SK-
dc.contributor.authorMao, X-
dc.contributor.authorWong, SWK-
dc.contributor.authorNg, TH-
dc.contributor.authorKo, FCF-
dc.contributor.authorKwong, EML-
dc.contributor.authorTang, AHN-
dc.contributor.authorNg, IOL-
dc.contributor.authorCai, SH-
dc.contributor.authorYun, JP-
dc.contributor.authorYam, JWP-
dc.date.accessioned2021-08-21T03:31:58Z-
dc.date.available2021-08-21T03:31:58Z-
dc.date.issued2021-
dc.identifier.citationCancer Research, 2021, v. 81 n. 13, p. 3679-3692-
dc.identifier.issn0008-5472-
dc.identifier.urihttp://hdl.handle.net/10722/302127-
dc.description.abstractLipid 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.-
dc.languageeng-
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/-
dc.relation.ispartofCancer Research-
dc.titleSuppression of ACADM-mediated fatty acid oxidation promotes hepatocellular carcinoma via aberrant Cav1/SREBP1 signaling-
dc.typeArticle-
dc.identifier.emailTey, SK: szekeong@hku.hk-
dc.identifier.emailMao, X: susanmao@hku.hk-
dc.identifier.emailNg, TH: tonyng93@hku.hk-
dc.identifier.emailKo, FCF: bokcf@hku.hk-
dc.identifier.emailTang, AHN: alextang@pathology.hku.hk-
dc.identifier.emailNg, IOL: iolng@hku.hk-
dc.identifier.emailYam, JWP: judyyam@pathology.hku.hk-
dc.identifier.authorityMao, X=rp02828-
dc.identifier.authorityTang, AHN=rp02468-
dc.identifier.authorityNg, IOL=rp00335-
dc.identifier.authorityYam, JWP=rp00468-
dc.description.naturepostprint-
dc.identifier.doi10.1158/0008-5472.CAN-20-3944-
dc.identifier.pmid33975883-
dc.identifier.scopuseid_2-s2.0-85109007488-
dc.identifier.hkuros324190-
dc.identifier.volume81-
dc.identifier.issue13-
dc.identifier.spage3679-
dc.identifier.epage3692-
dc.identifier.isiWOS:000670539900021-
dc.publisher.placeUnited States-

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